Peptoid compounds

ABSTRACT

The invention relates to new peptoid compounds of formula (I), as well as their use in the treatment of bacterial infections, such as those caused by vancomycin resistant microorganisms, and to compositions thereof.

This invention relates to novel peptoid compounds, methods for preparingthem and their use as antibiotics.

The death rate from infectious diseases in the developed world hasincreased over the last decade. This has been due to a number offactors, including increasing mobility of people from developedcountries to less developed countries, increasing age of the generalpopulation, increasing numbers of transplant, cancer and AIDS patientswho have lowered immunities to bacterial infections and the increasingnumbers of bacterial species that have become multiply resistant toantibacterial drugs.¹⁻³

The vancomycin group of antibiotics represent one of the last lines ofdefence against methicillin-resistant Staphylococcus aureus and otherGram-positive microorganisms.⁴⁻⁶ These antibiotics interfere withcell-wall biosynthesis by binding to the D-Ala-D-Ala terminus of thedisaccharyl pentapeptide of the peptidoglycan of the bacterial cellwall, resulting in cell death.⁴⁻⁶ Recently vancomycin resistant bacteriahave appeared. These bacteria have been identified as having aD-Ala-D-lactate terminus rather than a D-Ala-D-Ala terminus of thepeptidoglycan. Vancomycin has a much lower affinity (ca. 1000 folddecrease in affinity) for the D-Ala-D-lactate terminus in vancomycinresistant bacteria and consequently it is much less effective as anantibiotic.⁴⁻⁶

The binding sites of vancomycin to the D-Ala-D-Ala terminus of bacterialcells have been well characterised. The D-O-E ring moiety of thevancomycin molecule is critical for binding to the D-Ala-D-Ala terminusof bacterial cells and the binding includes a number of hydrogen bondinginteractions.⁴⁻⁶ The more complex left-hand side of the vancomycinmolecule has recently been shown to be critical for conformationalcontrol of the peptide moiety binding side.⁷

Biphenomycin A and B^(8,9) have also been found to be potent antibioticsand are particularly active against Gram-positive bacteria BiphenomycinA has also been found to have low toxicity in mice.⁸ The biphenomycinsare structurally much simpler than vancomycin, The biphenomycins have abiphenyl group instead of a diphenyl ether as found in vancomycin, andhave only one cyclic polypeptide ring and no sugar moieties. Thebiphenomycins also inhibit cell wall synthesis but, unlike vancomycin,not through binding to the D-Ala-D-Ala terminus of the disaccharylpentapeptide of the peptidoglycan of the bacterial cell wall.⁹

There is a need for new compounds which are useful in the treatment ofbacterial infections, especially those caused by vancomycin resistantmicroorganisms.

According to one aspect of the invention there is provided a compound ofthe formula (I):

-   -   wherein    -   A is an aromatic or heteroaromatic ring system or partially or        fully reduced derivatives thereof;    -   Q is hydrogen, C₁–C₁₂ straight chain, branched or cyclic alkyl        substituted with one or more hydroxy groups, or a mono- or        di-saccharide moiety;    -   Z is —CR¹⁰R¹¹—, —NR¹²—, —C(O)O—, —C(O)NR¹²— or —O—, where R¹⁰        and R¹¹ are independently selected from hydrogen, hydroxy, C₁–C₆        alkyl, C₆–C₁₀ aryl, C₁–C₆ alkoxy and —N(R¹³)₂ and where each R¹³        is independently selected from hydrogen and C₁–C₆ alkyl, and        where R¹² is selected from hydrogen and C₁–C₆ alkyl;    -   R¹ is selected from hydrogen, hydroxy, C₁–C₆ alkyl, C₁–C₆        alkoxy, —N(R¹³)₂ and —N(R¹²)—COR¹⁴; where R¹² and R¹³ are as        defined above, and where R¹⁴ is selected from hydrogen, hydroxy,        C₁–C₆ alkyl, C₁–C₆ alkoxy and —NR¹²;    -   R² is independently selected from hydrogen, hydroxy, C₁–C₆        alkyl, C₁–C₆ alkoxy, —N(R¹³)₂ and —N(R¹²)—COCHR^(2a)R^(2b);        where R^(2a) and R^(2b) are independently selected from        hydrogen, hydroxy, C₁–C₆ alkyl, C₁–C₆ alkoxy, —N(R¹³)₂ and        —N(R¹²)—COR¹⁴ where R¹², R¹³ and R¹⁴ are as defined above;    -   R³, R⁴ and R⁵ are independently selected from hydrogen, C₁–C₆        alkyl and α side chains of α-amino acids or their enantiomers or        their derivatives;    -   R⁶ is —CO₂R¹⁵, —CONHR¹⁶, —CONHOR¹⁶, —CONHNHR¹⁶, —SO₂N(R¹⁶)₂,        —SO₂R¹⁷ or —P(O)(OR¹⁸)(OR¹⁸) where each R¹⁵, R¹⁶, R¹⁷ and R¹⁸ is        independently selected from hydrogen, C₁–C₆ alkyl, C₃–C₇        cycloalkyl, C₆–C₁₀aryl and C₇–C₁₀ arylalkyl;    -   B is an α-amino acid residue, a β-amino acid residue or an        α,α-disubstituted amino acid residue, such residue forming amide        linkages with the adjacent molecules;    -   W is —O— or CR¹⁰R¹¹ where R¹⁰ and R¹¹ are as defined above;    -   Y is an optionally substituted amino group, a moiety containing        an optionally substituted amino group or a salt thereof;

-   -    is a single or double bond;    -   R⁷ and R^(8a) are hydrogen or are absent if

-   -    is a double bond; and    -   R^(8b) and R⁹ are hydrogen, and X is selected from        (CR¹⁰R¹¹)_(u), —(CR¹⁰R¹¹)_(u)—CH═CH—, —NR¹²(CR¹⁰R¹¹)_(u)—,        —(CR¹⁰R¹¹)_(u)NR¹²—, —O(CR¹⁰R¹¹)_(u)— or —(CR¹⁰R¹¹)_(u)O—, where        R¹⁰, R¹¹ and R¹² are as defined above; or    -   R^(8b) and R⁹ together form a covalent bond between X and the        carbon to which R^(8b) is attached, and X is selected from        (CR¹⁰R¹¹)_(x), —NR¹²(CR¹⁰R¹¹)_(x)—, —(CR¹⁰R¹¹)_(x)NR¹²—,        —O(CR¹⁰R¹¹)_(x)—, —O(CR¹⁰R¹¹)CH═CH— or —(CR¹⁰R¹¹)_(x)O—, where        R¹⁰, R¹¹ and R¹² are as defined above;    -   n, m, r and t are independently selected from 0 or 1;    -   s is an integer selected from 0 to 3;    -   p is an integer selected from 0 to 6, provided that when W is        —O—, p is at least 1; and    -   u, x and q are independently selected from 0 to 4;    -   and salts and pharmaceutically acceptable derivatives thereof.

The term “aromatic or heteroaromatic ring system” as used herein refersto a monoaryl, monoheteroaryl, or bridged, bonded or fused di- orpoly-aryl or heteroaryl group and their atropisomers and to which X andZ may be attached at any ring position. Examples of fused di- orpoly-aryl or heteroaryl groups include naphthene, fluorene,phenanthrene, indole, indazole, benzimidazole, carbazole, quinoline andisoquinoline, dibenzazepine and dibenzazocine.

Examples of bridged or bonded di- or poly-aryl or heteroaryl groupinclude groups consisting of two or more aromatic carbocyclic orheterocyclic systems, such as benzene, naphthene, pyridine, pyrimidine,quinoline, isoquinoline, indole, indazole, and benzimidazole, or thelike, joined by a covalent bond, and/or bridging group or groups, of oneor more atoms such as —O—, —CH₂—, —NH—, —SO₂—. Examples of bonded di- orpoly-aryl or heteroaryl systems include biphenyl, binaphthyl,biquinolyl, bi-isoquinolyl, bi-indole, bi-benzimidazole,phenyl-isoquinolyl, phenyl-quinolyl, phenyl-naphthyl, phenyl-indole,phenyl-benzimidazole, phenyl-indazole, phenyl-pyridine,phenyl-pyrimidine, naphthyl-pyridine, naphthyl-pyrimidine,naphthyl-isoquinolyl, naphthyl-quinolyl, naphthyl-indole,naphthyl-benzimidazole, naphthyl-indazole, quinolyl-isoquinolyl,quinolyl-indole, quinolyl-indazole, quinolyl-benzimidazole,indole-indazole, indole-benzimidazole, indazole-benzimidazole and thelike, and their atropisomers. The two aryl or heteroaryl groups may belinked at any position.

The aromatic or heteroaromatic groups or partially or fully reducedderivatives thereof may optionally be substituted with one or more C₁–C₆alkyl, C₁–C₆ thioalkoxy, hydroxy, C₁–C₆ alkoxy, amino, C₁–C₆ alkylamino,C₁–C₆ dialkylamino, halo, nitro, nitrile, sulphonylsulphonamide oralkyl- or aryl-sulphonyl, C₁–C₆ haloalkyl (for example trifluoromethyl)or carboxy groups. Preferably, the aromatic or heteroaromatic groups orpartially or fully reduced derivatives are unsubstituted or have fromone to four substituents selected from methyl, hydroxy, methoxy, amino,halo, or triftuoromethyl. Any nitrogen atoms in the heteroaromaticgroups may be protected by protecting groups such as t-butoxycarbonyl(BOC), 2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc), benzyl, acetyl,carbobenzyloxy and the like (see “Protective Groups in OrganicSynthesis” Theodora Greene and Peter Wuts, third edition, WileyInterscience, 1999).

Preferred aromatic and heteroaromatic ring systems include1,1′-binaphthyl, especially where the binaphthyl is substituted at the 2and 2′ positions with substituents selected from C₁–C₃ alkyl, C₁–C₃alkoxy, or arylalkyl, indole, phenyl, and N-protected or unprotectedcarbazole. Particularly preferred aromatic ring systems are 3,3′-linked1,1′-binaphthyl, where substitution of X and Z are at the 3 and3′-positions respectively (“3,3′-linked binaphthyl compounds”)particularly those which are 2,2′-C₁–C₃ alkoxy substituted, 2,2′-linked1,1′-binaphthyl where substitution of X and Z are at the 2 and 2′positions (“2,2′-linked binaphthyl compounds”), 3,6-linked 9H-carbazole(“3,6-linked 9H-carbazole compounds”), 1,3-linked indole (“1,3-linkedindole compounds”) and 1,4-linked phenyl (“1,4-linked phenylcompounds”)systems.

As used herein the term “atropisomer” refers to an enantiomer of acompound that exhibits conformational axial chirality.

As used herein the term “monosaccharide moiety” refers to a simple sugarsubstituent derived from a monosaccharide or a derivative thereof. Themonosaccharide may be a naturally occurring monosaccharide moiety, ormay be a substituted, protected or otherwise derivatised analogue of anaturally occurring monosaccharide. The monosaccharide may be mono, di-or triphosphated, and may be in its fully oxygenated form, or a deoxyform. Examples of monosaccharides from which the monosaccharide moietymay be derived include, but are not limited to abequose, iduronic acid,allose, lyxose, altrose, mannose, apiose, muramic acid, arabinose,neuraminic acid, arabinitol, N-acetylneuraminic acid, 2-deoxyribose,N-acetyl-2-deoxyneur-2-enaminic acid, fructose, N-glycoloylneuraminicacid, fucose, 3-deoxy-D-manno-oct-2-ulosonic acid, fucitol, rhamnose,galactose, 3,4-di-O-methylrhamnose, galactosamine, psicose,N-acetylgalactosamine, quinovose, β-D-galactopyranose 4-sulfate, ribose,glucose, ribose 5-phosphate, glucosamine, ribulose,2,3-diamino-2,3-dideoxy-D-glucose, sorbose, glucitol, tagatose,N-acetylglucosamine, talose, glucuronic acid, xylose, ethylglucopyranuronate, xylulose, gulose, 2-C-methylxylose, and idose.

As used herein the term “disaccharide moiety” refers to a sugarsubstitient composed of two glycosidically linked monosaccharides, orderivatives thereof. Examples of suitable disaccharide moieties include,but are not limited to, sucrose, lactose and maltose.

As used herein the term “optionally substituted amino group” refers toan unsubstituted amino group (NH₂) or an amino group substituted on thenitrogen atom with up to two substituents and salts thereof. The term“moiety containing an optionally substituted amino group” refers togroups that contain an amino group (NH₂) or an amino group substitutedon the nitrogen atom with up to two substituents. Examples of optionalsubstituents include C₁–C₆ alkyl, C₃–C₇ cycloalkyl, C₆–C₁₀ aryl andsuitable nitrogen protecting groups (see “Protective Groups in OrganicSynthesis” Theodora Greene and Peter Wuts, third edition, WileyInterscience, 1999). Preferably, the amino group is capable of carryinga positive charge at biological pH. In a preferred form of theinvention, Y is selected from a group consisting of: —N(R¹³)₂,—N(R¹²)—COR¹⁴, —NR¹³C(═NR¹³)N(R¹³)₂, —C(═NR¹³)N(R¹³)₂,—NR¹³C(═O)N(R¹³)₂, —N═NC(═NR¹³)N(R¹³)₂, NR¹³NR¹³C(═O)NHN(R¹³)₂,—NR¹³C(═)NHN(R¹³)₂, wherein R¹² and each R¹³ is independently selectedfrom hydrogen and C₁–C₆ alkyl and R¹⁴ is selected from hydrogen,hydroxy, C₁–C₆ alkyl, C₁–C₆ alkoxy and NR₁₂; and 3–8-memberedN-containing cyclogroup such as piperidinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl or piperazinyl, wherein the 3–8-memberedN-containing cyclogroup can be attached via a nitrogen or carbon atom.Preferred Y groups include optionally substituted guanidino[—NHC(═NH)NH₂], amidino [—C(═NH)NH₂], ureido [—NHC(═O)NH₂], carbazono[—N═NC(═)NHNH₂], carbazido [—NHNHC(═O)NHNH₂] and semicarbazido[—NHC(═O)NHNH₂] and amino (NH₂).

As used herein the term “C₁–C₆ alkyl” refers to straight chain orbranched alkyl groups having from 1 to 6 carbon atoms. Examples of suchgroups include methyl, ethyl, n-propyl, isopropyl and n-butyl.

As used herein the term “C₃–C₇ cycloalkyl” refers to cyclic alkyl groupshaving from 3 to 7 carbon atoms. Examples of such groups includecyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

As used herein the term “C₆–C₁₀ aryl” refers to carbocyclic aromaticsystems having from 6 to 10 carbon atoms. Examples of such groupsinclude phenyl and naphthyl.

As used herein the term “C₇–C₁₀ arylalkyl” refers to carbocyclicaromatic systems having 6 carbon atoms bonded to a C₁–C₄ alkyl group. Anexample of an arylalkyl group is a benzyl group.

As used herein the term “C₁–C₆ alkoxy” refers to straight chain orbranched alkoxy groups having from 1 to 6 carbon atoms. Examples of suchgroups include methoxy, ethoxy, n-propoxy, isopropoxy and differentbutoxy isomers.

The term α side chain of an α-amino acid includes the α-R group of anaturally occurring α-amino acid and may be selected from —CH₃,—(CH₂)₃NHC(═NH)NH₂, —CH₂CONH₂, —CH₂CO₂H, —CH₂SH, —(CH₂)₂CONH₂,—(CH₂)₂CO₂H, —CH₂(4-imidazole), —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂,—(CH₂)₃NH₂, —(CH₂)₄NH₂, —(CH₂)₂SCH₃, —CH₂Ph, —CH₂OH, —CH(CH₃)OH,—CH₂(3-indolyl), —CH₂(4-hydroxyphenyl) and —CH(CH₃)₂. This term alsoincludes the includes α-R groups of non-naturally occurring α-amino acidsuch as those found in homoarginine, homoserine, homocysteine,norvaline, norleucine or amidino derivatives. For example such α-sidechains include —(CH₂)₄NHC(═NH)NH₂, —(CH₂)₂OH, —(CH₂)₂SH, —CH₂CH₂CH₃,—(CH₂)₃CH₃, or (CH₂)_(v)C(═NH)NH₂ where v is an integer from 1 to 4.Other derivatives may include α-side chains in which hydroxy, thiol oramino groups are protected with suitable hydroxy, thiol or aminoprotecting groups (see “Protective Groups in Organic Synthesis” TheodoraGreene and Peter Wuts, third edition, Wiley Interscience, 1999).

B is an α-amino acid residue, a β-amino acid residue or anα,α-disubstituted amino acid residue. Suitable α-amino acids includethose derived from naturally occurring α-amino acids and non-naturallyoccurring α-amino acids. Examples of suitable α-amino acids include D-and L-α-amino acid residues derived from alanine, arginine,homoarginine, asparagine, aspartic acid, cysteine, homocysteine,glutamine, glutamic acid, glycine, histidine, isoleucine, leucine,norleucine, lysine, methionine, phenylalanine, serine, homoserine,threonine, tryptophan, tyrosine, proline, valine and norvaline. Othersuitable α-amino acid residues may have a side chain containing anamidino group, for example, (CH₂)_(v)C(═NH)NH₂ where v is an integerfrom 1 to 4. D- or L-alanyl, D-lysinyl, D-arginyl and D-homoarginylresidues are particularly preferred. Suitable β-amino acids includeH₂NC(R¹)R²C(R³)R⁴CO₂H where R¹, R², R³, R⁴ can be H and any of thesubstituents described above for the α-amino acids, and all possiblestereoisomers. Suitable α,α-disubstituted amino acids include any of theabove α-amino acids having a further substituent in the α-position.Suitable substituents include C₁–C₆ alkyl, hydroxy, C₁–C₆ alkoxy, amino,C₁–C₆ alkyl amino, C₁–C₆ dialkylamino, (CH₂)_(v)NH₂, (CH₂)_(v)NHC₁–C₆alkyl, (CH₂)_(v)N(C₁–C₆alkyl)₂, (CH₂)_(v)NHC(═NH)NH₂, (CH₂)_(v)OH,(CH₂)_(v)OC₁–C₆alkyl.

Preferred compounds of the present invention include:

-   benzyl    (aR/S,2S,5R)-8-acetamido-2-allyl-9-{3-[3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl]}-3,6-diaza-5-(4-{[(tert-butoxy)carbonyl]amino}butyl)-4,7-dioxononanoate-   (aR/S,7R,10S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-ene    hydrochloride.-   (aR/S,7R,10S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane    hydrochloride-   (aR/S,7R,10S)-4-acetamido-6,9-diaza-10-benzyloxycarbonyl-7-(4-{[(tert-butoxy)carbonyl]amino}butyl)-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-ene-   methyl    (aR/S,2S,5R)-8-acetamido-2-allyl-9-[3-(3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl)]-3,6-diaza-5-(3-guanidinopropyl)-4,7-dioxononanoate    hydrochloride-   (aR/S,7S,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-ene    hydrochloride-   (aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-ene    hydrochloride-   (aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane    hydrochloride-   Methyl    (2S,5S,8R/S)-8-acetamido-2-allyl-9-[6-allyl-9-tert-butoxycarbonyl-9H-carbazol-3-yl]-3,6-diaza-5-{3-[(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-guanidino]propyl}-4,7-dioxononanoate-   6-Acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane    HCl (9S,12S)-   6-Acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane    HCl (9R,12S)-   6-Acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane    HCl (9R,12S)-   6-Acetamido-9-(4-aminobutyl)-8,11-diaza-1-tert-butoxycarbonyl-14-ene-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane    HCl (9S,12S)-   6-Acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane    HCl (9S,12S)-   Methyl    (2S,5S,8R/S)-8-Acetamido-5-(4-aminobutyl)-3,6-diaza-9-{9-[(4-methoxyphenyl)methyl]-6-propyl-9H-carbazol-3-yl}-4,7-dioxo-2-propylnonanoate    hydrochloride-   6-Acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane    HCl (9R,12S)-   methyl    (aR/S,2S,5R)-2-allyl-5-[2-({[(2′-allyloxy-1,1′-binaphthoxymethyl]carbonyl}amino)-3-aza-9-guanidino-4-oxononanoate    hydrochloride-   (aR,S,7R,10S)-6,9-diaza-3,15-dioxa-5,8-dioxo-7-(4-guanidinobutyl)-10-methoxycarbonyl-1(1,2),2(1,2)-dinaphthalenacyclopentadecaphane-12-ene    hydrochloride-   methyl    (aS/R,2S,5R)-2-allyl-10-(2′-allyloxy-1,1′-binaphth-2-oxy)-5-(4-aminobutyl)-3,6-diaza-4,7-dioxodecanoate    hydrochloride-   methyl    (aS/R,2S,5R)-2-allyl-10-(2′-allyloxy-1,1′-binaphth-2-oxy)-3,6-diaza-5-(4-guanidinobutyl)-4,7-dioxodecanoate    hydrochloride-   (aR/S,9R,12S)-8,1-diaza-9-(4-guanidinobutyl)-12-methoxycarbonyl-1(1,2),2(1,2)-dinaphthalena-3,17-dioxa-7,10-dioxoheptadecaphane-15-ene    hydrochloride

It will be appreciated that the compounds of the present invention havemore than one asymmetric centre, and therefore are capable of existingin more than one stereoisomeric form. Some of the compounds may alsoexist as geometric isomers. Furthermore, some compounds of the inventionmay also have conformational axial chirality resulting in atropisomers.The invention extends to each of these forms individually and tomixtures thereof, including racemates. The isomers may be separatedconventionally by chromatographic methods or using a resolving agent.Alternatively the individual isomers may be prepared by asymmetricsynthesis using chiral intermediates, reagents or catalysts.

The salts of the compound of formula (I) are preferably pharmaceuticallyacceptable, but it will be appreciated that non-pharmaceuticallyacceptable salts also fall within the scope of the present invention,since these are useful as intermediates in the preparation ofpharmaceutically acceptable salts. The pharmaceutically acceptable saltsmay include conventional non-toxic salts or quaternary ammonium salts ofthese compounds, which may be formed, e.g. from organic or inorganicacids or bases. Examples of such acid addition salts include, but arenot limited to, those formed with pharmaceutically acceptable acids suchas acetic, propionic, citric, lactic, methanesulphonic,toluenesulphonic, benzenesulphonic, salicyclic, ascorbic, hydrochloric,orthophosphoric, sulphuric and hydrobromic acids. Base salts includes,but is not limited to, those formed with pharmaceutically acceptablecations, such as sodium, potassium, lithium, calcium magnesium, ammoniumand alkylammonium. Also, basic nitrogen-containing groups may bequaternised with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chlorides, bromides and iodides; dialkylsulfates like dimethyl and diethyl sulfate; and others.

Pharmaceutically acceptable derivatives may include any pharmaceuticallyacceptable salt, hydrate, prodrug, or any other compound which, uponadministration to a subject, is capable of providing (directly orindirectly) a compound of formula (I) or an antibacterially activemetabolite or residue thereof. For example, compounds where a hydroxygroup on the Q moiety has been replaced with a phosphate ester arewithin the scope of pharmaceutically acceptable derivatives.

The term “prodrug” is used in its broadest sense and encompasses thosederivatives that are converted in vivo to the compounds of theinvention. Such derivatives would readily occur to those skilled in theart, and include N-α-acyloxy amides, N-(acyloxyalkoxy carbonyl) aminederivatives and α-acyloxyalkyl esters of phenols and alcohols. A prodrugmay include modifications to one or more of the functional groups of acompound of the invention.

Throughout this specification the phrase “a group which is capable ofbeing converted in vivo” used in relation to another functional groupincludes all those functional groups or derivatives of such groups whichupon administration into a mammal may be converted into the statedfunctional group. Those skilled in the art may readily determine whethera group may be capable of being converted in vivo into the statedfunctional group using routine enzymatic or animal studies.

Preferred compounds of the invention have the formula (IA):

wherein A, Q, Z, R^(2a), R^(2b), R³, B, W, Y, R⁴, R⁵, R⁶, R⁷, R^(8a),R^(8b), R⁹, X, r, s, n, m, p q and t are as defined above.

Preferably one or more of the following definitions apply to preferredcompounds:

-   -   Q is hydrogen;    -   A is 2,2′-linked 1,1′-binaphthyl, 3,3′-linked        2,2′-dimethoxy-1,1′-binaphthyl, phenyl preferably 1,4-linked,        indolyl preferably 1,3-linked, fluorenyl or 9H-carbazole        preferably 3,6-linked;    -   Z is —O— or —CR¹⁰R¹¹—, more preferably —O— or —CH₂—;    -   R¹ is hydrogen or hydroxy;    -   R₂ is hydrogen, hydroxy or NHC(═O)CHR^(2a)R^(2b), preferably        hydrogen or NHC(═O)CH₃;    -   R₃ is hydrogen;    -   B is absent or a D- or L-alanyl residue, a D- or L-lysinyl, a D-        or L-arginyl residue or a D- or L-homoarginyl residue;    -   W is absent or is CH₂;    -   Y is NH₂, NHC(═NH)NH₂ or salts thereof;    -   R₄ is hydrogen;    -   R₅ is hydrogen;    -   R₆ is —CO₂R¹⁵, where R¹⁵ is C₁–C₆ alkyl or C₇–C₁₀ arylalkyl,        most preferably R¹⁵ is methyl or benzyl;    -   R^(8b) and R⁹ are hydrogen and X is —(CR¹⁰R¹¹)_(u)—, —CH═CH—        —O(CR¹⁰R¹¹)CH═CH—, or —CR¹⁰R¹¹—CH═CH— where R¹⁰ and R¹¹ are        hydrogen and u is an integer selected from 2 or 3;    -   R^(8b) and R⁹ together form a covalent bond between X and the        carbon to which R^(8b) is attached and X is —CR¹⁰R¹¹—, where R¹⁰        and R¹¹ are hydrogen.

Particularly preferred compounds in which A is a carbazole moiety are:

-   6-acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane    HCl (9R,12S),-   methyl    8-acetamido-3,6-diaza-5-[3-guanidinopropyl]-4,7-dioxo-2-propyl-9-[3-(6-propyl)-9H-carbazole]nonanoate    HCl (2S,5R),-   6-acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane    HCl (9R,12S),-   methyl    8-acetamido-5-[4-aminobutyl]-3,6-diaza-4,7-dioxo-2-propyl-9-[3-(6-propyl)-9H-carbazole]nonanoate    HCl (2S,5R),-   6-acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane    HCl (9S,12S),-   6-acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane    HCl (9S,12S),-   6-acetamido-9-(4-aminobutyl)-8,11-diaza-14-ene-12-methoxycarbonyl-7,10-dioxo-[12](4,17)-1H-carbazolophane    HCl (9R,12S),-   6-acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane    HCl (9R,12S),-   6-acetamido-9-(4-aminobutyl)-8,11-diaza-1-tert-butoxycarbonyl-14-ene-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane    HCl (9S,12S),-   6-acetamido-9-(4-aminobutyl)-8,11-diaza-1-tert-butoxycarbonyl-1    2-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane HCl    (9S,12S),-   6-acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-1-(4-methoxyphenylmethylene)-7,10-dioxo-[12](3,6)-1H-carbazolophane    HCl (9S,12S),-   6-acetamido-9-(4-aminobutyl)-8,11-diaza-4-ene-12-methoxycarbonyl-1-(4-methoxyphenylmethylene)-7,10-dioxo-[12](3,6)-1H-carbazolophane    HCl (9S,12S),-   6-acetamido-9-(4-aminobutyl)-8,11-diaza-14-ene-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane    HCl (9S,12S),-   6-acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane    HCl (9S,12S),-   methyl    8-acetamido-5-[4-aminobutyl]-3,6-diaza-9-[3-(9-methoxyphenylmethylene)-6-propyl-9H-carbazole]-4,7-dioxo-2-propylnonanoate    HCl (2S,5S)

Particularly preferred compounds in which A is a 2,2′-disubstitutedbinaphthyl moiety are the compounds prepared in Examples 15 and 21.

Compounds of formula (I) as described above, may be prepared by reactinga compound of formula (II)

wherein L is OH or an activating group; with a compound of formula (III)

wherein B is either H or an amino acid having a free amino group; underappropriate conditions. Unless otherwise defined, A, Q, X, Z, B, W, Y,R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R^(8a), R^(8b), R⁹, n, m, p, q, r, s and tin formulae (II) and (III) are as defined in formula (I).

The compound of formula (I) prepared by the coupling of compounds offormulae (II) and (III) may be further transformed using conventionalapproaches to provide other compounds of formula (I).

Conveniently, the reaction between compounds of formulae (II) and (III)is based on forming an amide bond and may be conducted using approachesroutinely used in peptide synthesis. For example, the coupling reactionof an amine with a carboxylic acid (L=OH) or an activated carbonylcarbon such as an acyl chloride, acyl azide or an anhydride (L=Cl, N₃,OC(O)R).

Compounds of formula (II) may be conveniently prepared from an aromaticor heteroaromatic ring system carrying any of:

-   -   (a) desired substituents; or    -   (b) functional groups which may be converted into desired        substituents using conventional approaches known to those        skilled in the art; or    -   (c) appropriately activated positions on the nucleus of the ring        system such that desired substituents may be placed on the ring        system using conventional approaches known to those skilled in        the art.

In addition the ring system includes a position that may be convertedinto the group —(X)_(t)R⁹, and a position where the side chain to bereacted with (III) may be formed. These positions may be functionalgroups or may be appropriately activated positions on the ring systemsuch as to allow conversion into functional groups using conventionalapproaches known to those skilled in the art. For example, functionalgroups include halogen, hydroxyl, amino, alkoxycarbonyl, and alkenyl.Examples of suitably activated positions include those which may behalogenated, hydroxylated, oxidised to a carbonyl group, alkylated oracylated.

Suitable aromatic or heteroaromatic ring systems may be commerciallyavailable or be readily prepared from commercially available ringsystems or ring system precursors.

The side chain to be reacted with a compound of formula (III) may beformed using any suitable approach readily ascertainable to thoseskilled in the art. Conveniently, a haloalkyl group on the ring systemmay be alkylated to form the side chain, in some cases after furthermodification. The side chain includes appropriate functionality to allowfor the reaction between compounds of formulae (II) and (III).Preferably, this is based on forming an amide bond and may be conductedusing approaches routinely used in peptide synthesis, for example, thereaction of an amine with an appropriately activated carbonyl carbon.Those skilled in the art can readily determine appropriate methodologyto build the desired side chain.

Where appropriate, protecting groups may be used to mask certainpositions on the compound of formula (II) so as to avoid or limitunwanted side reactions.

Compounds of formula (III) may be prepared using approaches familiar tothose skilled in the art of peptide chemistry or simple modifications ofthose approaches. Those skilled in the art can readily determineappropriate methodology to build the desired compound of formula (III).

Where appropriate protecting groups may be used to mask certainpositions on the compound of formula (III) so as to avoid or limitunwanted side reactions.

Preferably, the compound of formula (III) includes a free amino groupand the compound of formula (II) includes a free carboxylic acid or anactivated carbonyl carbon that may be reacted under appropriateconditions to form an amide bond.

Compounds of formula (I) where R^(8b) and R⁹ together form a covalentbond between X and the carbon to which R^(8b) is attached areconveniently formed by cyclisation of the corresponding non-cyclisedcompound. Cyclisation may be achieved using any ring closing reactionknown to those skilled in the art. For example, where the bond betweenCHR⁷ and CHR^(8a)R^(8b) is a double bond, and —(X)_(t)R⁹ includes analkenyl bond then ring closure may conveniently be performed using aring closing metathesis reaction. The resulting cyclised alkene may bereadily reduced to an alkyl bond using conventional approaches.

Examples of these general approaches are described in more detail in theexperimental section.

The compounds of the present invention may be useful in the treatment ofbacterial infections in mammals, particularly humans. They areparticularly useful for treating infections caused by Gram positivebacteria In particular, the compounds of the invention are useful fortreating infections caused by Gram positive bacteria such asEnterococcus faecium, Staphylococcus aureus, Staphylococcus epidermis,Klebsiella pneumoniae, Streptococcus pneumoniae, includingmultiresistant strains such as vancomycin resistant Staphylococcusaureus and methicillin-resistant Staphylococcus aureus.

Accordingly in a further aspect the invention provides a method for thetreatment of bacterial infection in a mammal comprising the step ofadministering an effective amount of a compound (I).

The invention also provides the use of a compound of formula (I) in themanufacture of a medicament for the treatment or prophylaxis ofbacterial infections.

The compounds of the invention are administered to the mammal in atreatment effective amount. As used herein, a treatment effective amountis intended to include at least partially attaining the desired effect,or delaying the onset of, or inhibiting the progression of, or haltingor reversing altogether the onset or progression of the bacterialinfection.

As used herein, the term “treatment effective amount” relates to anamount of compound which, when administered according to a desireddosing regimen, provides the desired therapeutic activity. Dosing mayoccur at intervals of minutes, hours, days, weeks, months or years, orcontinuously over any one of these periods. Suitable dosages lie withinthe range of about 0.1 ng per kg of body weight to 1 g per kg of bodyweight per dosage. The dosage is preferably in the range of 1 ng to 1 gper kg of body weight per dosage, such as is in the range of 1 mg to 1 gper kg of body weight per dosage. Suitably, the dosage is in the rangeof 1 mg to 500 mg per kg of body weight per dosage, such as 1 mg to 200mg per kg of body weight per dosage, or 1 mg to 100 mg per kg of bodyweight per dosage. Other suitable dosages may be in the range of 1 mg to250 mg per kg of body weight, including 1 mg to 10, 20, 50 or 100 mg perkg of body weight per dosage or 10 mg to 100 mg per kg of body weightper dosage. The compounds of the invention may be administered in asingle dose or a series of doses.

Suitable dosage amounts and dosing regimens can be determined by theattending physician and may depend on the particular condition beingtreated, the severity of the condition, as well as the general health,age and weight of the subject being treated.

While it is possible that, for use in therapy, a compound of theinvention may be administered as the neat chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt or derivative thereof together with one or more pharmaceuticallyacceptable carriers thereof and, optionally, other therapeutic and/orprophylactic ingredients. The carrier(s) must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not deleterious to the recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation or insufflation.The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalcompositions and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, or capsules filled with thesame, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. Formulations containingten (10) milligrams of active ingredient or, more broadly, 0.1 to twohundred (200) milligrams, per tablet, are accordingly suitablerepresentative unit dosage forms. The compounds of the present inventioncan be administered in a wide variety of oral and parenteral dosageforms. It will be obvious to those skilled in the art that the followingdosage forms may comprise, as the active component, either a compound ofthe invention or a pharmaceutically acceptable salt or derivative of thecompound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavoured base, usually sucroseand acacia or tragacanth; pastilles comprising the active ingredient inan inert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multidose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomising spray pump. To improve nasal delivery andretention the compounds according to the invention may be encapsulatedwith cyclodextrins, or formulated with their agents expected to enhancedelivery and retention in the nasal mucosa.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).

Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 1 to 10 microns or less.Such a particle size may be obtained by means known in the art, forexample by micronization.

When desired, formulations adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Liquids or powders for intranasal administration, tablets or capsulesfor oral administration and liquids for intravenous administration arepreferred compositions.

The invention will now be described with reference to the followingexamples which illustrate some preferred aspects of the presentinvention. However, it is to be understood that the particularity of thefollowing description of the invention is not to supersede thegenerality of the preceding description of the invention.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

EXAMPLES

General Experimental Information

Melting point (mp) determinations were carried out on a Gallenkamp orReichert melting point apparatus. Chemical ionisation (CI) and electronimpact (EI) mass spectra were obtained on a Shimadzu QP-5000 massspectrometer by a direct insertion technique with an electron beamenergy of 70 eV. Electrospray (ES) mass spectra were obtained on a VGQuattro spectrometer. High-resolution mass spectra (HRMS) weredetermined on a VG Autospec spectrometer or on a micromass QT^(o)Fspectrometer. The m/z values are stated with their peak intensity as apercentage in parentheses. Proton and carbon nuclear magnetic resonance(NMR) spectra were determined with a Varian Unity 300 MHz spectrometeror with a Varian Unity 400 MHz spectrometer where specified. Spectrawere recorded in (D)chloroform (CDCl₃) using chloroform or TMS as theinternal standard, unless specified otherwise. Chemical shifts (δ) inppm were measured relative to the internal standard. Where samplesexhibited several isomers, the chemical shifts for the major form aregiven since the major and minor isomers could not be separated, andoverlapping peaks made it difficult to specify all the chemical shiftsfor the minor isomer(s). Analytical thin layer chromatography (TLC) wascarried out on Merck Kieselgel 60 F₂₅₄ precoated aluminium plates with athickness of 0.25 mm. All column chromatography was performed underflash conditions on Merck Kieselgel 60 (230–400 mesh). Chromatographysolvent mixtures were measured by volume. Organic solvent extracts weredried with anhydrous magnesium sulfate, and the solvent removed underreduced pressure with a Büchi rotary evaporator. Solvents were purifiedand dried by standard techniques. All compounds were judged to be ofgreater than 90% purity based upon ¹H NMR and TLC analysis. Startingmaterials and reagents were purchased from Sigma-Aldrich Pty Ltd andwere used as received. Petroleum spirit refers to the 40–60° C. bp rangematerial. The Grubbs' ruthenium catalyst used was specificallybenzylidene-bis(tricyclohexylphosphine)-dichlororuthenium.

Abbreviations Ac acetyl Boc tert-butyloxycarbonyl DCM dichloromethaneDMF N,N-dimethylformamide DMSO dimethyl sulfoxide HCl hydrochloric acidEtOAc ethyl acetate MeOH methanol Pmc2,2,5,7,8-pentamethylchroman-6-sulfonyl PS petroleum spirit TFAtrifluoracetic acid THF tetrahydrofuran DMAP 4-dimethylaminopyridine DCC1,3-dicyclohexylcarbodiimide HMPA hexamethylphosphoramide TMEDAN,N,N′,N′-tetramethylethylenediamine Fmoc 9-fluorenylmethoxycarbonyl

Example Synthesis of Peptides Example 1 Protection of the CarboxylicAcid of L-Allylglycine

L-Allylglycine (0.600 g) was dissolved in dry methanol (7 mL) and cooledin an ice bath. Thionyl chloride (2 equivalents) was added dropwise andthe reaction warmed to room temperature and left to stir for 3 hours atroom temperature after which the solvent was removed by rotaryevaporation. The residue was redissolved in methanol and re-evaporatedseveral times to give a 90% yield of a white low melting point solid.

MS ES 130 [RNH³]⁺. ¹H NMR 400 MHz (CDCl₃) δ8.58, 3H, br s, NH₃; 5.8, 1H,br s, H2, 5.32, 1H,d, J=15.6 Hz, H1; 5.26, 1H, d, J=6.8 Hz, H1′; 4.20,1H, m, H4; 3.80, 3H, s, OCH ₃; 2.88, 2H, m, H3,H3′. ¹³C NMR 75 MHzδ169.2, CO₂CH₃; 130.1, C2; 121.5, C1; 53.3, OCH₃; 53.0, C4; 34.5, C3.

Example 2 Preparation of Nα-Fmoc-Nε-Boc-D-Lysine-L-Allylglycine MethylEster

L-Allylglycine methyl ester HCl (0.706 g) was suspended in drydichloromethane (10 mL) and Fmoc-D-Lysine(BOC) OH (1 equiv.) was addedunder N₂ with stirring, followed by DMAP (0.1 equiv) anddiisopropylethyl amine (1.0 equiv). The mixture was cooled to 0° C. andDCC (1.0 equiv) added. The reaction was left to stir at ambienttemperature over night. The suspension was filtered through celite andthe solids washed with cold DCM, the filtrate and washings combined andwashed twice with water then the solvent was removed by rotaryevaporation. The residue was then chromatographed in 2% CH₃OH/DCM togive 76% yield of a pale cream flaky solid.

HRMS Calc. mass 580.3023. Found 580.3018 [M+H], C₃₂H₄₂N₃O₇. ¹H NMR(CDCl₃) δ7.76, 2H, d, J=7.5 Hz, H17,17′; 7.59, 2H, d, J=6.9 Hz, H20,20′;7.40, 2H, t, J=7.2 Hz, H19,19′; 7.31, 2H, ddd, J=9.0, 7.2, 1.2 Hz,H18,18′; 6.7, 1H, br.d, J=6.6 Hz, NH; 5.63, 2H, br. m, NH, H2; 5.10, 1H,d, J=5.4 Hz, H1; 5.05, 1H, s, H1′; 4.65, 2H, H4, NH; 4.38, 2H, d, J=6.6Hz, H14, H14′; 4.21, 2H, H15, H8; 3.71, 3H, s, OCH₃; 3.11, 2H, d, J=6.0Hz, H12,H12′; 2.52, 2H, m, H3,H3′; 1.85, 2H, m; 1.68, 2H, m; 1.48–1.25,2H, m; 1.43, 9H, s, t-Bu.

Example 3 Deprotection of the α Amino Group ofNα-Fmoc-Nε-Boc-D-Lysine-L-Allylglycine Methyl Ester

Fmoc-D-Lys(BOC)-L-Allylgly-methyl ester (0.631 g) was dissolved in 10 mLdry acetonitrile and 20 mol % of piperidine in acetonitrile was added.The flask was fitted with a condenser and the reaction stirred under N₂at 30° C. over night. The solvent was then removed to give a pale creamoily semi solid which was chromatographed on silica in 5% methanol indichloromethane to give the deprotected product (0.389 g (58% yield)) asa cream oil.

MS ES 358.1 [M+H]⁺ ¹H NMR 300 MHz (CDCl₃) δ7.79, 1H, d, J=8.1 Hz, NH;5.66, 1H, m, H2; 5.16, 1H, d, J=5.7 Hz, H1; 5.11, 1H, d, J=0.9 Hz, H1′;4.91, 1H, NH; 4.30, 1H, m, H4; 3.74, 3H, s, OCH₃; 3.33, 1H, br s, H8;3.12, 2H, d, J=6.0 Hz, H12, H12′; 2.56, 2H, m, H3, H3′; 1.87–1.26, 8H,m, H9, H9′, H10, H10′, H11, H11′, NH₂; 1.43, 9H, s, 3CH₃.

Compounds Based on a 3,3′-Substituted Binaphthyl Nucleus

Example 4 Preparation of (+/−)-2,2′-dimethoxy-1,1′-binaphthyl

(+/−)-1,1′-Bi-2,2′-naphthol (10.13 g, 35 mmol) was dissolved in acetone(300 mL, 0.12 M). Potassium carbonate (16.69 g, 121 mmol) and methyliodide (22 mL, 353 mmol) were added and the mixture heated to refluxunder nitrogen for 48 h. The cooled reaction mixture was evaporated todryness, the residue taken up in acetone (60 mL) and water (360 mL) thenstirred for 7.5 h. The solid was collected and dried under vacuum at100° C. overnight yielding (+/−)-2,2′-dimethoxy-1,1′-binaphthyl as acolourless solid (10.76 g, 97%), (lit.¹⁰ 224–225° C.).

¹H NMR δ3.75, s, 6H, OCH₃; 7.10, br d, J=8 Hz, 2H; 7.20, dt, J=1.5, 8Hz, 2H; 7.30, ddd, J=1.5, 7, 8 Hz, 2H; 7.45, d, J=9 Hz, 2H; 7.86, d,J=7.5 Hz, 2H; 7.96, d, J=9 Hz, 2H, ArH.

Example 5 Preparation of(+/−)-3,3′-diiodo-2,2′-dimethoxy-1,1′-binaphthyl

To a solution of TMEDA (1.0 mL, 6.6 mmol) in diethyl ether (50 mL) wasadded a solution of n-butyl lithium (1.6 M in hexanes, 4.4 mL, 7.0mmol). The resulting solution was stirred for 15 min at roomtemperature. (+/−)-2,2′-Dimethoxy-1,1′-binaphthyl (1.038 g, 3.3 mmol)was added as a solid to the reaction mixture which was then stirred for3 h at room temperature. The reaction mixture was then cooled to −80° C.and iodine (2.8 g, 11.0 mmol) was added over several minutes using anaddition tube. The reaction mixture was allowed to gradually warm toroom temperature and was stirred overnight. The reaction mixture wasstirred with a solution of saturated aqueous sodium sulfite (addedcautiously) for 4 h at room temperature. The reaction mixture waspartitioned between dichloromethane (200 mL) and water (200 mL). Theorganic layer was dried (MgSO₄/Na₂SO₄), filtered and the filtrateevaporated to dryness. The resulting deep yellow oil was purified byflash column chromatography (5% ethyl acetate/hexane) to yield(+/−)-3,3′-diiodo-2,2′-dimethoxy-1,1′-binaphthyl as a pale yellowcrystalline solid (0.954 g, 51%).

¹H NMR δ3.41,s, 6H, 2×OCH₃; 7.07, d, J=8 Hz, 2H; 7.26, ddd, J=1.5, 7, 8Hz, 2H; 7.40, ddd, J=1, 7, 8 Hz, 2H; 7.79, d, J=8 Hz, 2H, ArH; 8.53, s,2H, ArH4, 4′. ¹³C NMR δ61.1, OCH3; 92.3, 125.3, 4° ArC; 125.6, 125.75,126.9, 127.05, 132.2, 4° ArC; 133.8, 4° ArC; 139.9, 154.5, 4° ArC. m/z(CI, +ve) 567 (100%). C₂₂H₁₆I₂O₂+H⁺ requires 567.

The by-product from this reaction is(+/−)-3-iodo-2,2′-dimethoxy-1,1′-binaphthyl, which is separated from(+/−)-3,3′-diiodo-2,2′-dimethoxy-1,1′-binaphthyl using chromatography.

Example 6 Preparation of(+/−)-3-iodo-2,2′-dimethoxy-3′-methyl-1,1′-binaphthyl

To a −80° C. solution of(+/−)-3,3′-diiodo-2,2′-dimethoxy-1,1′-binaphthyl (2.016 g, 3.6 mmol) inTHF (dry, distilled, 80 mL, 0.044 M) was added n-butyl lithium (2.8 mL,3.9 mmol) dropwise. The reaction mixture turned yellow and was stirredfor 1 h before the addition of methyl iodide (dry, distilled, 0.35 mL,5.6 mmol). The reaction mixture was allowed to gradually warm to roomtemperature. After stirring for a further 3 h saturated aqueous ammoniumchloride solution (4 drops) was added. The reaction mixture wasevaporated to dryness, the residue taken up in diethyl ether and washedwith water. The organic layer was dried (MgSO₄), filtered and thefiltrate evaporated to dryness to give a pale yellow solid. Purificationof the crude material by flash column chromatography (4% ethylacetate/hexane) yielded(+/−)-2,2′-dimethoxy-3-iodo-3′-methyl-1,1′-binaphthyl.

¹H NMR δ2.55, s, 3H, CH₃; 3.36, s, 6H, OCH₃; 7.06, d, J=8 Hz, 1H; 7.12,d, J=8 Hz, 1H; 7.16–7.42, m, 2H, ArH; 7.80, t, J=8 Hz, ArH; 7.81, s,3H,ArH4″; 8.52, s, ArH4.

The product also contained(+/−)-3,3′-diiodo-2,2′-dimethoxy-1,1′-binaphthyl (10%) and(+/−)-2,2′-dimethoxy-3,3′-dimethyl-1,1′-binaphthyl (8%).

Other reaction products seperated by chromatography were(+/−)-2,2′-dimethoxy-3-iodo-1,1′-binaphthyl and(+/−)-2,2′-dimethoxy-3-methyl-1,1′-binaphthyl.

Example 7 Preparation of(+/−)-3-bromomethyl-3′-iodo-2,2′-dimethoxy-1,1′-binaphthyl

(+/−)-3-Iodo-2,2′-dimethoxy-3′-methyl-1,1′-binaphthyl (1.737 g, 3.8mmol) was dissolved in carbon tetrachloride (100 mL) andN-bromosuccinimide (1.316 g, 7.4 mmol) was added. The mixture was heatedto reflux followed by external irradiation of the pyrex flask with a 500W mercury lamp for 1 h. The cooled reaction mixture was filtered (toremove succinimide), the filtrate evaporated to dryness to give a redsolid. The residue was purified by flash column chromatography (4% ethylacetate/hexane) to yield a colourless crystalline solid (1.130 g) thatwas a mixture containing(+/−)-3-bromomethyl-3′-iodo-2,2′-dimethoxy-1,1′-binaphthyl (0.942 g,46%).

¹H NMR δ3.36, s, 3H, OCH₃; 3.40, s, 3H, OCH₃; 4.72 d, J=9.9 Hz, 1H,CH_(2A); 4.91, d, J=9.9 Hz, 1H,CH_(2B); 7.08, d, J=8 Hz, 1H; 7.18, d,J=8 Hz, 1H; 7.23–7.44, m, 4H; 7.80, d, J=8 Hz, 1H; 7.88, d, J=8 Hz, 1H,ArH; 8.07, s, 1H, ArH4 and 8.54, s, 1H, ArH4′.

The other component was found to be(+/−)-3-bromo-3′-bromomethyl-2,2′-dimethoxy-1,1′-binaphthyl (0.188 g,10%).

Example 8 Preparation of ethyl(+/−)-3-[3-(2,2′-dimethoxy-3′-iodo-1,1′-binaphthyl)]-2-[(diphenylmethylene)amino]propanoate

To a −10° C. solution of HMPA (0.7 mL, 4.02 mmol) and diisopropylamine(0.24 mL, 1.71 mmol) in THF (dry, distilled, 40 mL) was addedn-butyllithium (1.32 M in hexanes, 1.4 mL, 1.85 mmol). The pale yellowsolution was stirred for 10 min then cooled to −78° C.

To this solution was added a solution of ethylN-(diphenylmethylene)glycinate (0.450 g, 1.68 mmol) in THF (dry,distilled, 20 mL) using a cannula and precooling the addition solutionby running the drops down the side of the receiving flask. The resultingmixture was stirred for 30 min then a solution of3-bromomethyl-2,2′-dimethoxy-3′-iodo-(+/−)-1,1′-binaphthyl (0.895 g,1.68 mmol) in THF (dry, distilled, 40 mL) was added using a cannula. Thereaction mixture was allowed to slowly warm to room temperature andstirred over night. The yellow solution was quenched with aqueousammonium chloride solution (1 mL). The reaction mixture was evaporatedto dryness to give a yellow oil that contained ethyl(+/−)-3-[3-(2,2′-dimethoxy-3′-iodo-1,1′-binaphthyl)]-2-[(diphenylmethylene)amino]propanoate.The residue was used without further purification, due to the presenceof HMPA.

¹H NMR δ1.21, t, J=5 Hz, 3H, CH₃; 3.00, s, 3H, OCH₃; 3.20, s, 3H, OCH₃;3.40, dd, J=7, 10 Hz, 1H, CH_(2A); 3.71, dd, J=3, 10 Hz, 1H, CH_(2B);4.11–4.22, m, 2H, OCH₂; 4.50, q, J=3 Hz, 1H, α-CH; 6.82, d, J=5 Hz, 1H,NH; 7.78–6.98, m, 19H, ArH; 8.49, s, 1H, ArH.

Example 9 Preparation of ethyl(+/−)-2-amino-3-[3-(2,2′-dimethoxy-3′-iodo-1,1′-binaphthyl)]propanoatehydrochloride salt

To a solution of the crude alkylated product from Example 8 (1.208 g,1.68 mmol) in diethyl ether (30 mL) was added 3% aqueous hydrogenchloride solution (15 mL, 4.6 mmol). The mixture was stirred at RTovernight and gave a yellow oil underneath the aqueous layer underneatha yellow organic layer. The mixture was evaporated to dryness, thesticky yellow residue was taken up in ethanol and evaporated to dryness.This was repeated twice more. The final residue was dried under highvacuum then freeze dried. The crude product was used without furtherpurification.

¹³C NMR δ13.8, 13.9, ArCH₃; 33.0, 33.6, ArCH₂; 53.2, 53.7, OCH₂; 61.0,61.1, 61.2, 62.3, OCH₃; 92.3, α-CH; 117.4, 124.1, 124.2, 125.1, 125.3,125.5, 125.6, 125.8, 126.0, 126.2, 126.5, 126.7, 126.75, 126.9, 127.05,127.65, 127.85, 128.2, 130.0, 130.4, 131.3, 132.0, 132.1, 132.4, 132.8,132.9, 133.3, 134.8, 133.9, 134.1, 139.7 (×2), 152.5, 154.4, 154.7,154.9, ArC; 168.6, 169.0, C═O.

Example 10 Preparation of ethyl(+/−)-2-acetylamino-3-[3-(2,2′-dimethoxy-3′-iodo-1,1′-binaphthyl)]propanoate

The residue obtained after acid hydrolysis containing the binaphthylsalt obtained in Example 9 (0.993 g, 1.68 mmol) was dissolved indichloromethane (dry, distilled, 100 mL). The solution was stirred withMgSO₄ (anhydrous) briefly then cooled in an ice/salt bath. Triethylamine(0.70 mL, 5.02 mmol) was added, followed by acetic anhydride (0.4 mL,4.24 mmol) and DMAP, after stirring for 5 min. The reaction mixture wasallowed to warm to room temperature and was stirred overnight. To thereaction mixture was added a solution of 3% aqueous hydrochloric acid(50 mL) and dichloromethane (50 mL). The aqueous layer was removed andextracted with dichloromethane. The combined organic layers were washedwith a solution of 3% aqueous hydrochloric acid (×1), a solution of 1:1aqueous saturated lithium chloride and water (×2) then water (×1). Thesolution was dried (MgSO₄) and the filtrate evaporated to dryness togive a yellow liquid. The crude product was purified by squat columnchromatography (10% ethyl acetate/hexane→ethyl acetate) to yield ethyl(+/−)-2-acetylamino-3-[3-(2,2′-dimethoxy-3′-iodo-1,1′-binaphthyl)]propanoateas a pale yellow solid (0.75 g, 75% from(+/−)-3-bromomethyl-3′-iodo-2,2′-dimethoxy-1,1′-binaphthyl)(ave. 91%yield per step).

¹H NMR δ1.25, t, J=7 Hz, 3H, CH₃; 1.98, s, 3H, COCH₃; 3.26, s, OCH₃;3.28, s, 3H, OCH₃; 3.30–3.42, m, ArCH₂; 4.23, m, OCH₂; 4.73, q, J=7 Hz,1H, α-CH; 6.79, d, J=7 Hz, 1H, NH; 7.05–7.82, ArH; 7.86, s, 1H, ArH4;8.535, s, 1H, ArH4′.

Example 11 Preparation of ethyl(+/−)-2-acetylamino-3-[3-(3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl)]propanoate

To a solution of the binaphthyl derivative obtained from Example 10(0.740 g, 1.24 mmol) in 1,4-dioxane (dry, 40 mL) was added palladiumchloride (0.025 g, 0.14 mmol) and triphenylphosphine (0.136 g, 0.52mmol). The solution was deoxygenated with argon for 10 min thenallyltributyltin (0.39 mL, 1.26 mmol) was added. The resulting mixturewas heated at reflux for 5 h. After cooling the solution was filteredthrough celite and evaporated to dryness. The residue was purified bysquat column chromatography, to remove stannanes, then flash columnchromatography (50% ethyl acetate/hexane) to give a mixture thatcontained ethyl(+/−)-2-acetylamino-3-[3-(3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl)]propanoateas a clourless oil (0.54 g, 85%).

¹H NMR δ0.92, t, J=7 Hz; 1.26, t, J=7 Hz, 3H,CH₃; 1.98, s; 2.04, s, 3H;COCH₃; 3.17, s, 3H, OCH₃; 3.235, s, 3H, OCH₃; 3.25–3.33, m, 2H, CH₂;3.58–3.72, br m, 2H, CH₂; 4.12, q, J=7 Hz, (OCH₂); 4.21, q, J=7 Hz, 2H,OCH₂; 4.71, q, J=7 Hz, α-CH; 4.84, q, J=5 Hz, 1H, α-CH; 5.125–5.19, m,2H, ═CH₂; 6.08–6.22, m, 1H, CH═; 6.78, d, J=7 Hz; 6.91, d, J=7 Hz, 1H,NH; 7.14–7.26, m, 4H, ArH; 7.35–7.46, m, 2H, ArH; 7.81–7.85, m, 4H, ArH.m/z (CI, +ve) 512 (100%). C₃₂H₃₃NO₅+H⁺ requires 512.

The other product in this mixture is ethyl(+/−)-2-acetylamino-3-[3-(3′-bromo-2,2′-dimethoxy-1,1′-binaphthyl)]propanoate.

Example 12 Preparation of(+/−)-2-acetylamino-3-[3-(3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl)]propanoicacid

The binaphthyl derivative obtained in Example 11 (0.522 g, 1.02 mmol)was dissolved in THF (22 mL) and cooled in an ice/water bath. To thissolution was added a solution of lithium hydroxide monohydrate (0.196 g,4.67 mmol) in water (9 mL). The mixture was allowed to gradually warm toroom temperature and was stirred for 5 h. To the reaction mixture wasadded diethyl ether, the aqueous layer was washed with ether and thecombined ether layers extracted with water (×2). The combined aqueouslayers were acidified (3% aq. HCl), extracted with diethyl ether (×3)and dried (MgSO₄). The filtrate was evaporated to dryness to give(+/−)-2-acetylamino-3-[3-(3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl)]propanoicacid as a white solid (0.462 g, 94%).

¹H NMR δ2.07, s, 3H, COCH₃; 3.07, s, 3H, OCH₃; 3.20, s, 3H, OCH₃;3.28–3.77, m, 2×CH₂; 4.55, 2×t, J=5 Hz, 1H, α-CH; 5.11–5.19, m, 2H,═CH₂; 6.07–6.20, m, 1H, CH═; 7.16–7.56, m, 6H, ArH; 7.74, br s, 1H, NH;7.84, d, J=8 Hz, ArH; 7.88, s, 4H, ArH4, 4′.

Example 13 methyl(aR/S,2S,5R)-8-acetamido-2-allyl-9-{3-[3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl]}-3,6-diaza-5-(4-{[(tert-butoxy)carbonyl]amino}butyl)-4,7-dioxononanoate

The binaphthyl derivative obtained from Example 12 (0.258 g, 0.53 mmol)was dissolved in dichloromethane (dry, 3 mL) and a solution of thedipeptide obtained from Example 3 (freshly deprotected) (0.22 g, 0.61mmol) in dichloromethane (3 mL) was added. To the resulting solution wasadded 4-dimethylaminopyridine (crystal) and then the solution was cooledin an ice/water bath. To the chilled solution was added1,3-dicyclohexylcarbodiimide (0.111 g, 0.54 mmol). The reaction mixturewas allowed to warm to room temperature and was stirred overnight. Tothe reaction mixture was added dichloromethane (10 mL) which was thenfiltered through celite. The filtrate was evaporated to give the amideas a pale yellow crystalline solid (0.404 g, 92%). m/z (ES, +ve) 823(M+H⁺, product, 32%), 723 (823-Boc, 8), 565 (11), 428 (19), 358 (21),302 (26) and 225 (DCU+H⁺, 100). C₄₇H₅₈N₄O₉+H⁺ requires 823.

Example 13A Preparation of benzyl(aR/S,2S,5R)-8-acetamido-2-allyl-9-{3-[3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl]}-3,6-diaza-5-(4-{[(tert-butoxy)carbonyl]amino}butyl)-4,7-dioxononanoate

The corresponding allylglycine benzyl ester of the compound of Example13 was prepared by similar methods as described above except that theappropriate benzyl precursor was used. The amino group of the lysineside chain was deprotected according to the procedure of Example 15 togive the target compound.

Example 13B benzyl(aR/S,2S,5R)-8-acetamido-2-allyl-9-{3-[3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl]}-5-(4-aminobutyl)-3,6-diaza-4,7-dioxononanoatehydrochloride

Prepared from the product obtained from Example 13 (0.0226 g, 0.025mmol) using the method as set out in Example 15. The product wasisolated as a pale yellow solid (0.014 g, 67%).

m/z (ES, +ve) 839 (M+CH₃CN, 1%), 837 (M+K⁺, 1), 799 (M+H⁺, 19), 626 (2),449 (4), 338 (6) and 225 (DCU+H⁺, 100).

Example 14 Preparation of(aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(4-{[(tert-butoxy)carbonyl]amino}butyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-ene

The binaphthyl derivative obtained in Example 13 (0.205 g, 0.25 mmol)was dissolved in dichloromethane (50 mL). The solution was deoxygenatedwith argon gas for 10 min before the addition ofbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.022 g, 0.027mmol). The reaction mixture was heated to reflux for 18 hours. Thecooled reaction mixture was evaporated to dryness and the resultingresidue purified by flash column chromatography to give three fractionseach of which contained different diasteriomeric cyclic products;

1) Pale yellow glass like solid (0.038 g). m/z (ES, +ve) 817 (M+Na⁺,4%), 795 (M+H⁺, 16), 593 (48) and 297 (O═P(C₆H₁₁)₃+H⁺, 100);

2) Light brown solid (0.041 g). m/z (ES, +ve) 795 (M+H⁺, 54%), 593 (35),297 (O═P(C₆H₁₁)₃+H⁺, 100), 145 (44), 104 (33) and 86 (64);

3) Very pale yellow glass like solid (0.073 g)(Total=0.152 g, 74%). m/z(ES, +ve) 795 (M+H⁺, 15%), 297 (O═P(C₆H₁₁)₃+H⁺, 29), 147 (32), 145 (66),106 (16), 104 (52) and 86 (100). C₄₅H₅₄N₄O₉+H⁺ requires 795.

Example 15 Preparation of(aR/S,7R,10S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-enehydrochloride

The protected diasteriomeric cyclic peptoids prepared in Example 14(0.073 g, 0.09 mmol) were dissolved in dichloromethane (2 mL) thentrifluoroacetic acid (2 mL) was added. The mixture was stirred at roomtemperature for 25 min. The mixture was evaporated to dryness, theresidue taken up in dichloromethane and evaporated to dryness again.This was repeated twice more. The residue was taken up indichloromethane (3 mL) and a solution of 1.0 M hydrogen chloride indiethyl ether (1 mL) was added. The resulting mixture was stirred atroom temperature for 10 min before being evaporated to dryness. Theresidue was taken up in dichloromethane and evaporated to dryness again.This was repeated twice more. The deprotected product was crystallisedfrom the residue with diethyl ether and dichloromethane. The product wasisolated using centrifugation to yield the deprotected cyclic product asa pale yellow crystalline solid (0.055 g, 82%). m/z (ES, +ve) 696.5(41%) and 695.8 (53) and 695.4 (M+H⁺, 73) (aggregates), 111 (48) and 60(100). C₄₀H₄₆N₄O₇+H⁺ requires m/z 695.3445. Found 695.3400.

Similarly other diastereomers were also obtained—(0.021 g, 60%) m/z (ES,+ve) 697 (32%) and 696 (100) and 695 (M+H⁺, 96) (aggregates),C₄₀H₄₆N₄O₇+H⁺ requires m/z 695.3445. found 695.3435; and (0.023 g, 60%),m/z (ES, +ve) 696 (9%), 695 (M+H⁺, 20); 111 (12) and 60 (100);C₄₀H₄₆N₄O₇+H⁺ requires m/z 695.3445. found 695.3427.

Example 15A(aR/S,7R,10S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphanehydrochloride

One of the isomers of the deprotected cyclized peptoid obtained fromExample 15 was dissolved in a mixture of dichloromethane (0.2 mL),methanol (0.5 mL) and water (0.2 mL). To this solution was added 10%Pd/C (0.001 g, 0.0009 mmol) and the reaction vessel was sealed. Thereaction mixture was stirred and the atmosphere inside the reactionvessel removed and replaced with an atmosphere of hydrogen. Thisprocedure was repeat twice. The reaction was stirred at room temperaturefor several days before removal of all solid material by passing thereaction mixture through a plug of celite (filter aid). The filtrate wasevaporated and gave the reduced deprotected cyclized peptoid as a whitesolid (0.001 g, 33%).

m/z (ES, +ve) 697 (M+H⁺, 100%); 316 (51), 288 (74).

Example 15B Preparation of(aR/S,7R,10S)-4-acetamido-6,9-diaza-10-benzyloxycarbonyl-7-(4-{[(tert-butoxy)carbonyl]amino}butyl)-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-ene

The corresponding benzyl ester of the compound of Example 15 wasprepared by similar methods as described above except that theappropriate benzyl precursor was used. Two isomers were isolated at theprotected cyclic peptide stage and these were seperately deprotected toprovide the desired products.

m/z (ES, +ve) 771 (M+H⁺, 100). m/z (ES, +ve) 771 (M+H⁺, 72%), 699 (7),59 (100) respectively.

Example 16 Coupling of(+/−)-2-acetylamino-3-[3-(3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl)]propanoicacid with Nε-Fmoc-L-lysine-L-allylglycine methyl ester

The binaphthyl derivative obtained in Example 12 (0.447 g, 0.92 mmol)was dissolved in dichloromethane (1 mL) and a solution of theNε-Fmoc-L-lysine-L-allylglycine methyl ester (freshly deprotected)(0.450 g, 0.94 mmol) in dichloromethane (2 mL) was added. To theresulting solution was added 4-dimethylaminopyridine (crystal) and thenthe solution was cooled in an ice/water bath. To the chilled solutionwas added 1,3-dicyclohexylcarbodiimide (0.195 g, 0.94 mmol). Thereaction mixture was allowed to warm to room temperature and was stirredovernight. To the reaction mixture was added dichloromethane (10 mL)which was then filtered through celite. The filtrate was evaporated todryness and the residue purified by flash column chromatography to givethe coupled product as an off white crystalline solid (0.474 g, 54%).

m/z (ES, +ve) 945 (M+H⁺, 36%) and 225 (DCU+H⁺, 100). C₅₇H₆₀N₄O₉+H⁺requires 945.

Example 17 Preparation of the Protected Cyclic Peptoid

The binaphthyl derivative obtained in Example 16 (0.470 g, 0.50 mmol)was dissolved in dichloromethane (120 mL). The solution was deoxygenatedwith argon gas for 10 min before the addition ofbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.022 g, 0.027mmol). The reaction mixture was heated to reflux for 18 h. The cooledreaction mixture was evaporated to dryness the resulting residuepurified by flash column chromatography (4% methanol/dichloromethane) togive the cyclic peptoid product as an off white crystalline solid (0.329g, 72%).

m/z (ES, +ve) 918 (4%), 917 (M+H⁺, 5), 593 (9), 522 (3) and 297 (100).C₅₅H₅₆N₄O₉+H⁺ requires 917.

Example 18 Preparation of the Deprotected Cyclic Peptoid

To the protected cyclic peptoid obtained in Example 17 (0.123 g, 0.13mmol) was added dry acetonitrile (9 mL). The mixture was warmed to 60°C. in a sealed system and a solution of 0.02 M piperidine inacetonitrile (0.54 mL) was added. The reaction mixture was heated at 60°C. for 43 h. The cooled mixture was filtered, and the filtrateevaporated to dryness to give a white solid. The solid was purified byflash column chromatography (10% methanol/dichloromethane, followed by10% methanol/dichloromethane containing 2% triethylamine). The isolatedproduct was dissolved in dichloromethane (5 mL) and 1.0 M hydrogenchloride in diethyl ether (0.5 mL) was added. The solution was stirredfor 10 min then evaporated to dryness and dried under high vacuum togive the deprotected cyclic peptoid product as a pale yellow crystallinesolid (0.048, 51%).

m/z (ES, +ve) 729 (30%), 695 (M+H⁺, 100) and 498 (25). C₄₀H₄₆N₄O₇+H⁺requires m/z 695.3445. Found 695.3419.

Example 19 Coupling of(+/−)-2-acetylamino-3-[3-(3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl)]propanoicacid with Nω-PMC-L-arginine-L-allylglycine methyl ester

The binaphthyl derivative obtained in Example 12 (0.127 g, 0.26 mmol)and Nω-PMC-L-arginine-L-allylglycine methyl ester (freshly deprotected)(0.150 g, 0.27 mmol) were dissolved in dichloromethane (dry, 1.5 mL). Tothe resulting solution was added 4-dimethylaminopyridine (crystal) andthen the solution was cooled in an ice/water bath. To the chilledsolution was added 1,3-dicyclohexylcarbodiimide (0.053 g, 0.25 mmol).The reaction mixture was allowed to warm to room temperature and wasstirred overnight. To the reaction mixture was added dichloromethane (10mL) which was then filtered through celite. The filtrate was evaporatedto dryness and the residue purified by flash column chromatography (4%methanol/dichloromethane) to give the protected arginine derivative as acolourless solid (0.176 g, 68%).

m/z (ES, +ve) 1056 (M+K⁺, 4%), 1040 (M+Na⁺, 16), 1018 (M+H⁺, 64), 1017(M⁺, 100), 920 (13), 624 (14) and 225 (24). C₅₆H₆₈N₆O₁₀S requires 1017.

Example 19A Preparation of methyl(aR/S,2S,5R)-8-acetamido-2-allyl-9-[3-(3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl)]-3,6-diaza-5-(3-guanidinopropyl)-4,7-dioxononanoatehydrochloride

Similarly to the procedures described above the D-arginyl version ofExample 19 was prepared. This was deprotected according to the procedureof Example 21 and isolated as a pale yellow solid.

Example 20 Preparation of the Protected Cyclic Peptoid

The binaphthyl derivative obtained in Example 19 (0.176 g, 0.17 mmol)was dissolved in dichloromethane (50 mL). The solution was deoxygenatedwith argon gas for 10 min before the addition ofbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.015 g, 0.017mmol). The reaction mixture was heated to reflux for 20 h. The cooledreaction mixture was evaporated to dryness and the resulting residuepurified by flash column chromatography (4% methanol/dichloromethane) togive the cyclic peptoid product as a light brown glass (0.132 g, 77%).

m/z (ES, +ve) 1011 (M+Na⁺) and 989 (M+H⁺). C₅₄H₆₄N₆O₁₀S+H⁺ requires 989.

Example 21 Preparation of(aR/S,7S,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-enehydrochloride

The cyclic peptoid obtained in Example 20 (0.047 g, 0.05 mmol) wasdissolved in dichloromethane (2 mL) then trifluoroacetic acid (2 mL) wasadded. The mixture was stirred at room temperature for 25 min. Themixture was evaporated to dryness, the residue taken up indichloromethane and evaporated to dryness again. This was repeated twicemore. The residue was taken up in dichloromethane (3 mL) and a solutionof 1.0 M hydrogen chloride in diethyl ether (1 mL) was added. Theresulting mixture was stirred at room temperature for 10 min beforebeing evaporated to dryness. The residue was taken up in dichloromethaneand evaporated to dryness again. This was repeated twice more. Thedeprotected product was crystallised from the residue with diethyl etherand dichloromethane. The deprotected product was isolated usingcentrifugation and yielded an off white solid (0.021 g, 58%).

m/z (ES, +ve) 724 (100%). C₄₀H₄₆N₆O₇+H⁺ requires m/z 723.3506. Found723.3488.

Example 21A Preparation of(aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-enehydrochloride

Similarly to the procedures described above the D-arginyl version ofExample 21 was prepared and the isomers of the deprotected cyclicpeptoid that contains a D-arginine residue were isolated as an off-whitesolid and a pale yellow solid respectively.

m/z (ES, +ve) 723 (M+H⁺, 15), 316 (28), 288 (78), 217 (100), 199 (79),111 (41) and m/z (ES, +ve) 723 (M+H⁺, 30), 316 (51), 288 (100), 217 (34)and 199 (45) respectively.

Example 21B Preparation of(aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphanehydrochloride

Preparation of a Reduced Cyclic Peptoid that Contains an D-ArginineResidue

The cyclized peptoid of Example 21A was dissolved in methanol (2 mL). Tothis solution was added 10% Pd/C (0.012 g, 0.01 mmol) and the reactionvessel was sealed. The reaction mixture was stirred and the atmosphereinside the reaction vessel removed and replaced with an atmosphere ofhydrogen. This procedure was repeat twice. The reaction was stirred atroom temperature for several days before removal of all solid materialby passing the reaction mixture through a plug of celite (filter aid).The filtrate was evaporated and gave the reduced cyclic peptoid as alight brown solid.

m/z (ES, +ve) 725 (M+H⁺, 19%), 394 (13), 316 (71), 288 (100), 180 (37)and 111 (47).

Example 22 Preparation of Cyclic Tetra Peptoid

This compound was prepared in a similar manner to the compound ofExample 18 but the aminoacyl moiety used in the coupling reactioncontained an additional alanine residue.

m/z (ES, +ve) 766.5 (100%), 767 (79) and 767.5 (58). C₄₃H₅₁N₅O₈+H⁺requires m/z 766.3816. found 766.3740.

Compounds Based on a 3,6-Substituted Carbazole Nucleus

The preparation of6-acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophaneHCl described in Examples 23 to 35 is shown schematically in Scheme 1.

Nomenclature for Carbazole Based Cyclic Peptoids6-acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophane

These compounds are named as carbozolophanes with the numbering of thecyclophane structure as shown above. The notation [12] refers to thelength of the atom chain attached to the heteroaromatic scaffold and thenotation (3,6) refers to where this 12-atom chain is attached to theparent 9H-carbazole unit.

Note: For examples 23–44, where samples exhibited several isomers[diastereoisomers, (E) or (Z) isomers and/or rotamers], the minor formis indicated by an asterisk in their NMR spectra.

Example 23 Preparation of 6-bromo-3-methyl-1,2,3,4-tetrahydrocarbazole

To a solution of 4-methylcyclohexanone (5.47 mL, 44.6 mmol), cyclohexane(70 mL) and glacial acetic acid (50 mL) was added 4-bromophenylhydrazinehydrochloride (10.0 g, 44.6 mmol) and the reaction mixture was refluxedfor 23 h under a nitrogen atmosphere. The cooled reaction mixture wasfiltered and the filtrate was evaporated. Diethyl ether was added andthe mixture was washed with a saturated sodium bicarbonate solution andthen water; the ether solution was dried and evaporated. The crudeproduct was recrystallised from ethanol over an ice bath, filtered,washed with cold PS and dried in vacuo to afford6-bromo-3-methyl-1,2,3,4-tetrahydrocarbazole (8.73 g, 33.1 mmol, 74%) asan off-white solid, mp 108–110° C.

¹H NMR, 400 MHz, (D₆)benzene, δ7.78, d, J=2 Hz, 1H, H-5; 7.41, dd, J=8,2 Hz, 1H, H-7; 6.77, d, J=8 Hz, 1H, H-8; 6.23, bs, 1H, NH; 2.53, dd,J=15, 5 Hz, 1H, H-4; 2.32–2.15, m, 2H, H-1, H-2; 2.01, dd, J=15, 9 Hz,1H, H-4; 1.73–1.61, m, 2H, H-2, H-3; 1.29, m, 1H, H-1; 0.99, d, J=7 Hz,3H, CH₃.

Example 24 Preparation of6-bromo-9-tert-butoxycarbonyl-3-methyl-1,2,3,4-tetrahydrocarbazole

A solution of 6-bromo-3-methyl-1,2,3,4-tetrahydrocarbazole obtained fromExample 23 (7.0 g, 26.5 mmol) in dry THF (25 mL) was added to sodiumhydride (1.17 g, 29.2 mmol) under a nitrogen atmosphere and the mixturewas stirred for 0.5 h at room temperature. A solution ofdi-tert-butyl-dicarbonate (8.67 g, 39.8 mmol) in dry THF (55 mL) wasadded and the reaction mixture was stirred for 20.5 h. The reactionsolvent was evaporated, ether was added and the ether mixture was washedwith water, dried and evaporated. The crude product was dissolved inethanol, the solvent evaporated to a minimal volume and the productrecrystallised over an ice bath. The recrystallised solid was filtered,washed with cold MeOH and dried in vacuo to afford6-bromo-9-tert-butoxycarbonyl-3-methyl-1,2,3,4-tetrahydrocarbazole (8.33g, 22.9 mmol. 86%) as an off-white solid, mp 122° C.

¹H NMR, (D₆)benzene, δ8.27, d, J=8.7 Hz, 1H, H-8; 7.61, d, J=2.1 Hz, 1H,H-5; 7.44, dd, J=8.7, 2.1 Hz, 1H, H-7; 3.06–2.94, m, 1H, H-1; 2.85–2.70,m, 1H, H-2; 2.36, dd, J=16, 5 Hz, 1H, H-4; 1.90–1.78, m, 1H, H-4; 1.65,m, 2H, H-2 and H-3; 1.38, s, 9H, C(CH₃)₃; 1.30–1.16, m, 1H, H-1; 0.96,d, J=6.6 Hz, 3H, CHCH ₃.

Example 25 Preparation of3-bromo-9-tert-butoxycarbonyl-6-methylcarbazole

To a mixture of6-bromo-9-tert-butoxycarbonyl-3-methyl-1,2,3,4-tetrahydrocarbazoleobtained in Example 24 (2.0 g, 5.49 mmol),2,3-dichloro-4,5-dicyano-1,4-benzoquinone (2.62 g, 11.5 mmol) andactivated 3 Å molecular sieves was added anhydrous benzene (17 mL) undera nitrogen atmosphere, and the mixture was refluxed for 20 h. The cooledreaction mixture was filtered and the filtrate evaporated. The crudeproduct was chromatographed (PS with gradient elution up to PS:DCM 3:1)to afford 3-bromo-9-tert-butoxycarbonyl-6-methylcarbazole (1.64 g, 4.56mmol, 83%) as a colourless solid. By-products were alsoobtained—6-bromo-9-tert-butoxycarbonyl-4-ethoxy-3-methylcarbazole (12mg, 0.030 mmol, 0.5%) was obtained as a colourless oil, and6-bromo-9-tert-butoxycarbonyl-1,2-dihydro-3-methylcarbazol-4-(3H)-one(52 mg, 0.14 mmol, 2.5%) was obtained as a pale yellow solid.

3-bromo-9-tert-butoxycarbonyl-6-methylcarbazole: mp 96° C. Rf: 0.66 inPS:DCM (2:1). ¹H NMR, δ8.14, d, J=9 Hz, 1H, H-1; 8.10, d, J=8.7 Hz, 1H,H-8; 7.99, d, J=2.1 Hz, 1H, H-4; 7.65, bs, W_(1/2) 4 Hz, 1H, H-5; 7.50,dd, J=8.9, 2 Hz, 1H, H-2; 7.27, dd, J=8.4, 1.8 Hz, 1H, H-7; 2.48, s, 3H,ArCH₃; 1.74, s, 9H, C(CH₃)₃.

6-bromo-9-tert-butoxycarbonyl-4-ethoxy-3-methylcarbazole: Rf: 0.58 inPS:DCM (2:1). ¹H NMR, δ8.32, d, J=2.1 Hz, 1H, H-4; 8.16, d, J=9 Hz, 1H,H-1; 7.91, d, J=8.4 Hz, 1H, H-8; 7.51, dd, J=8.9, 2 Hz, 1H, H-2; 7.27,d, J=8.7 Hz, 1H, H-7; 4.06, q, J=7.2 Hz, 2H, OCH ₂CH₃; 2.40, s, 3H,ArCH₃; 1.72, s, 9H, C(CH₃)₃; 1.55, t, J=7.2 Hz, 3H, OCH₂CH ₃.6-bromo-9-tert-butoxycarbonyl-1,2dihydro-3-methylcarbazol-4-(3H)-one: mp137° C.

Example 26 Preparation of3-bromo-6-bromomethyl-9-tert-butoxycarbonylcarbazole

A suspension of 3-bromo-9-tert-butoxycarbonyl-6-methylcarbazole obtainedfrom Example 25 (653 mg, 1.81 mmol) and recrystallisedN-bromosuccinimide (355 mg, 2.00 mmol) in carbon tetrachloride wasrefluxed under nitrogen with irradiation from a 150 W halogen lamp for2.5 h. The reaction mixture was cooled over an ice bath and filtered,and the filtrate evaporated. The crude product was chromatographed (PSwith gradient elution to PS:DCM 1:1) to afford3-bromo-6-bromomethyl-9-tert-butoxycarbonylcarbazole (551 mg, 1.26 mmol,69%) as a colourless solid, mp 150° C. (dec).

¹H NMR, 400 MHz, δ8.22, d, J=8.4 Hz, 1H, H-8; 8.16, d, J=8.8 Hz, 1H,H-1; 8.07, d, J=2 Hz, 1H, H-4; 7.93, d, J=1.6 Hz, 1H, H-5; 7.54, dd,J=8.8, 2 Hz, 1H, H-2; 7.50, dd, J=8.8, 2 Hz, 1H, H-7; 4.66, s, 2H, CH₂;1.73, s, 9H, CH₃.

Example 27 Preparation of diethyl2-acetamido-2-[3′-(6′-bromo-9′-tert-butoxycarbonyl)-carbazolylmethyl]-propanedioate

A solution of diethyl acetamidomalonate (225 mg, 1.04 mmol) in anhydrousDMSO (6 mL) was added to sodium hydride (44 mg, 1.09 mmol) under anitrogen atmosphere and the mixture was stirred at room temperature for1.5 h. After this period,3-bromo-6-bromomethyl-9-tert-butoxycarbonylcarbazole obtained fromExample 26 (500 mg, 1.14 mmol) was added and the reaction mixture wasstirred at room temperature for 0.5 h. The reaction mixture was dilutedwith diethyl ether, the ether mixture was washed with brine and thenwater several times. The water layers were extracted with diethyl ether,and the ether extracts were washed with water. Both ether solutions werecombined, dried and evaporated to afford diethyl2-acetamido-2-[3′-(6′-bromo-9′-tert-butoxycarbonyl)-carbazolylmethyl]-propanedioate(448 mg, 0.78 mmol, 75%) as a yellow solid, mp 158° C.

¹H NMR, 400 MHz, δ8.14, d, J=8 Hz, 2H, H-1′ and H-8′ (direct overlap);7.95, d, J=1.6 Hz, 1H, H-5′; 7.54, d, J=2 Hz, 1H, H-4′; 7.53, dd, J=8.8,2 Hz, 1H, H-7′; 7.10, dd, J=8.6, 2 Hz, 1H, H-2′; 6.53, s, 1H, NH; 4.28,q, J=7.2 Hz, 4H, OCH ₂CH₃; 3.79, s, 2H, ArCH₂; 2.05, s, 3H, COCH3; 1.72,s, 9H, C(CH₃)₃; 1.31, t, J=7.2 Hz, 6H, OCH₂CH ₃.

Example 28 Preparation of ethyl2-acetamido-3-[3′-(6′-bromocarbazole)]propanoate

A suspension of diethyl2-acetamido-2-[3′-(6′-bromo-9′-tert-butoxycarbonyl)-carbazylmethyl]-propanedioateobtained from Example 27 (310 mg, 0.54 mmol), lithium chloride (23 mg,0.54 mmol), distilled water (0.02 mL, 1.08 mmol) and DMSO (5 mL) wasrefluxed under a nitrogen atmosphere for 2 h. The cooled reactionmixture was diluted with ether, the ether mixture was washed with brineand then water. The ether layer was dried and evaporated to afford ethyl2-acetamido-3-[3′-(6′-bromocarbazole)]propanoate (181 mg, 0.45 mmol,83%) as a yellow solid, mp 175° C.

¹H NMR, δ8.49,s, 1H, NH; 8.05, d, J=1.8 Hz, 1H, H-5′; 7.69, s, W_(1/2) 4Hz, 1H, H-4′; 7.43, dd, J=8.6, 1.8 Hz, 1H, H-7′; 7.25, d, J=9 Hz, 1H,H-1′; 7.23, d, J=8.4 Hz, 1H, H-8′; 7.12, dd, J=8.3, 1.5 Hz, 1H, H-2′;6.05, d, J=7.5 Hz, 1H, NH; 4.90, dt, J=7.8, 6 Hz, 1H, CHN; 4.16, q,J=7.2 Hz, 2H, OCH ₂CH₃; 3.27, dd, J=14.1, 6.3 Hz, 1H, ArCH₂; 3.20, dd,J=14, 5.9 Hz, 1H, ArCH₂; 1.96, s, 3H, COCH₃; 1.22, t, J=7.2 Hz, 3H,OCH₂CH ₃.

Example 29 Alternative One-Pot Preparation of ethyl2-acetamido-3-[3′-(6′-bromocarbazole)]propanoate

A solution of diethyl acetamidomalonate (368 mg, 1.70 mmol) in anhydrousDMSO (10 mL) was added to sodium hydride (71 mg, 1.78 mmol) under anitrogen atmosphere and the mixture was stirred at room temperature for1.5 h. After this period,3-bromo-6-bromomethyl-9-tert-butoxycarbonylcarbazole obtained in Example26 (820 mg, 1.87 mmol) was added and the reaction mixture was stirred atroom temperature for 0.5 h. Lithium chloride (71 mg, 1.70 mmol) anddistilled water (0.06 mL, 3.40 mmol) were added and the reaction mixturewas refluxed for 1.75 h. The reaction mixture was diluted with ether,the ether mixture was washed with brine and then water, the combinedwater layers were extracted with ether, and these extracts were washedwith wafer. The combined ether layers were dried and evaporated and thecrude product was chromatographed (PS with gradient elution to DCM andfinally EtOAc) to afford ethyl 2-acetamido(6′-bromo-9′-ethyl)-3-carbazolepropanoate (56 mg, 0.13 mmol, 8%) as adark yellow oil, and ethyl2-acetamido-3-[3′-(6′-bromocarbazole)]propanoate (481 mg, 1.19 mmol,70%) as a pale yellow solid.

Ethyl 2-acetamido-3-[3′-(6′-bromo-9′-ethylcarbazole)]propanoate: ¹H NMR,δ8.11, d, J=1.8 Hz, 1H, H-5′; 7.73, s, W_(1/2) 4.7 Hz, 1H, H-4′; 7.51,dd, J=8.5, 2 Hz, 1H, H-7′; 7.30, d, J=8.4 Hz, 1H, H-1′; 7.24, d, J=8.4Hz, 1H, H-8′; 7.20, dd, J=8.4, 1.8 Hz, 1H, H-2′; 5.98, d, J=7.5 Hz, 1H,NH; 4.91, dt, J=7.8, 6 Hz, 1H, CHN; 4.29, q, J=7.2 Hz, 2H, NCH ₂CH₃;4.18, q, J=7.2 Hz, 2H, OCH ₂CH₃; 3.27, d, J=5.7 Hz, 2H, ArCH₂; 1.98, s,3H, COCH₃; 1.38, t, J=7.2 Hz, 3H, NCH₂CH ₃; 1.24, t, J=7.2 Hz, 3H,OCH₂CH ₃.

Example 30 Preparation of ethyl2-acetamido-3-[3′-(6′-allylcarbazole)]propanoate

To a glass, high-pressure tube containing ethyl2-acetamido-(6′-bromo)-3-carbazolepropanoate obtained in Examples 28 or29 (1.0 g, 2.48 mmol), palladium chloride (22 mg, 0.124 mmol) andtriphenylphosphine (130 mg, 0.496 mmol) was added anhydrous DMF (10 mL)followed by allyltributyltin (0.92 mL, 2.98 mmol). The tube was sealedunder nitrogen and the reaction mixture heated in a 110° C. oil bath for22 h. The cooled reaction mixture was diluted with diethyl ether, theether mixture was washed with brine and then water, and the ether layerwas dried and evaporated. The crude product was chromatographed (PS withgradient elution to DCM:EtOAc 2:1) to afford ethyl2-acetamido-3-[3′-(6′-allylcarbazole)]propanoate (823 mg, 2.26 mmol,91%) as a pale yellow solid, mp 100° C.

¹H NMR, δ8.13, bs, 1H, ArNH; 7.80, s, W_(1/2) 4.8 Hz, 1H, H-5′; 7.76, s,W_(1/2) 4.8 Hz, 1H, H-4′; 7.32, d, J=8.7 Hz, 1H, H-8′; 7.29, d, J=8.4Hz, 1H, H-1′; 7.22, dd, J=8.7, 1.2 Hz, 1H, H-7′; 7.10, dd, J=8.4, 1.5Hz, 1H, H-2′; 6.05, ddt, J=17, 10, 6.6 Hz, 1H, CH₂CH═CH₂; 5.96, d, J=8.4Hz, 1H, NHAc; 5.11, dd, J=15, 1.8 Hz, 1H, CH₂CH═CH ₂; 5.08, d, J=8.1 Hz,1H, CH₂CH═CH ₂; 4.90, dt, J=7.8, 6.3 Hz, 1H, CHN; 4.17, q, J=7.2 Hz, 2H,OCH ₂CH₃; 3.54, d, J=6.6 Hz, 2H, CH ₂CH═CH₂; 3.26, d, J=5.7 Hz, 2H,ArCH₂; 1.97, s, 3H, COCH₃; 1.23, t, J=7.2 Hz, 3H, OCH₂CH ₃.

Example 31 Preparation of ethyl2-acetamido-3-[3′-(6′-allyl-9′-tert-butoxycarbonylcarbazole)]propanoate

A suspension of ethyl 2-acetamido-3-[3′-(6′-allylcarbazole)]propanoateobtained in Example 30 (823 mg, 2.26 mmol) and cesium carbonate (1.47 g,4.52 mmol) in anhydrous DMF (20 mL) was stirred at room temperatureunder a nitrogen atmosphere for 15 min before a solution ofdi-tert-butyl-dicarbonate (739 mg, 3.39 mmol) in anhydrous DMF (6 mL)was added. The reaction mixture was stirred at room temperature for 20h. After this period the reaction mixture was diluted with ether, andthe ether mixture was washed with brine followed by water, and thendried and evaporated. The crude product was chromatographed (PS withgradient elution to DCM:EtOAc 5:1) to afford ethyl2-acetamido-3-[3′-(6′-allyl-9′-tert-butoxycarbonylcarbazole)]propanoate(820 mg, 1.77 mmol, 78%) as a pale yellow solid, mp 125° C.

¹H NMR, δ8.18, d, J=8.1 Hz, 1H, H-8′; 8.16, d, J=8.1 Hz, 1H, H-1′; 7.71,d, J=1.2 Hz, 1H, H-4′; 7.68, d, J=1.5 Hz, 1H, H-5′; 7.27, dd, J=8.5, 1.5Hz, 1H, H-2′; 7.17, dd, J=8.5, 1.8 Hz, 1H, H-7′; 6.03, ddt, J=16.5, 9.9,6.9 Hz, 1H, CH₂CH═CH₂; 5.11, dd, J=17.7, 1.8 Hz, 1H, CH₂CH═CH ₂; 5.10,dd, J=10.2, 1.8 Hz, 1H, CH₂CH═CH ₂; 4.90, dt, J=7.5, 6 Hz, 1H, CHN;4.17, q, J=7.2 Hz, 2H, OCH ₂CH₃; 3.52, d, J=6.6 Hz, 2H, CH ₂CH═CH₂;3.28, dd, J=14, 5.7 Hz, 1H, ArCH₂; 3.22, dd, J=14.1, 5.7 Hz, 1H, ArCH₂;1.98, s, 3H, COCH₃; 1.72, s, 9H, C(CH₃)₃; 1.23, t, J=7.2 Hz, 3H, OCH₂CH₃.

Example 32 Preparation of2-acetamido-3-[3′-[6′-allyl-9′-tert-butoxycarbonylcarbazole)]propanoicacid

To an ice-cold solution of ethyl2-acetamido-3-[3′-(6′-allyl-9′-tert-butoxycarbonylcarbazole)]propanoateobtained in Example 31 (787 mg, 1.70 mmol) in THF (50 mL) was added asolution of lithium hydroxide (440 mg, 10.5 mmol) in distilled water (20mL), and the reaction mixture was stirred at 0° C. for 3.5 h. After thisperiod the THF portion of the solvent was evaporated, the aqueousmixture remaining was diluted with distilled water and washed withether. The aqueous layer was acidified to pH<2 with a 10% HCl solutionand the product was extracted with diethyl ether, after adding asufficient amount of solid sodium chloride to the acidified mixture todissolve it. Finally, the ether extracts were dried and evaporated toafford2-acetamido-3-[3′-(6′-allyl-9′-tert-butoxycarbonylcarbazole)]propanoicacid (666 mg, 1.53 mmol, 90%) as a colourless solid, mp 177° C.

¹H NMR, (D₆)acetone, δ8.21, d, J=8.4 Hz, 1H, H-8′; 8.20, d, J=8.7 Hz,1H, H-1′; 7.96, d, J=1.2 Hz, 1H, H-4′; 7.89, d, J=0.9 Hz, 1H, H-5′;7.39, dd, J=8.4, 1.5 Hz, 2H, H-2′ and NH (concealed under ArH signal);7.33, dd, J=8.5, 1.8 Hz, 1H, H-7′; 6.07, ddt, J=16.9, 9.9, 6.9 Hz, 1H,CH₂CH═CH₂; 5.14, dd, J=17.2, 1.5 Hz, 1H, CH₂CH═CH ₂; 5.07, dd, J=9.9,1.5 Hz, 1H, CH₂CH═CH ₂; 4.80, m, 1H, CHN; 3.55, d, J=6.9 Hz, 2H, CH₂CH═CH₂; 3.34, dd, J=13.8, 5.4 Hz, 1H, ArCH₂; 3.15, dd, J=13.8, 8.1 Hz,1H, ArCH₂; 1.89, s, 3H, COCH₃; 1.76, s, 9H, C(CH₃)₃.

Example 33 Preparation of a Carbazole Peptoid Derivative

To a mixture of2-acetamido-3-[3′-(6′-allyl-9′-tert-butoxycarbonylcarbazole)]propanoicacid (84 mg, 0.192 mmol), methyl L-arg(Pmc)allylglycinate (106 mg, 0.192mmol) and 4-dimethylaminopyridine (1 crystal) was added dry DCM (3 mL)and anhydrous acetonitrile (5 mL). The mixture was warmed and stirredvigorously under nitrogen to give a translucent solution before1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (37 mg,0.192 mmol) was added. The reaction mixture was stirred at roomtemperature under nitrogen for 19.5 h. After this period the reactionsolvent was evaporated, DCM was added and the mixture was washed withbrine followed by water. The DCM layer was dried and evaporated and thenchromatographed (PS with gradient elution to DCM:MeOH 10:1). Thepurified product was triturated with PS from DCM to give the carbazolepeptoid derivative as a cream solid, mp 141–143° C. Rf: 0.60 in 10% MeOHin DCM.

¹H NMR, δ8.12, d, J=8.4 Hz, 1H, ArH; 8.10, d, J=8.4 Hz, 1H, ArH; 7.78,s, W_(1/2) 6 Hz, 1H, ArH; 7.66, s, W_(1/2) 4 Hz, 1H, ArH; 7.59, d, J=7.5Hz, 1H, NH; 7.29–7.19, m, 2H, ArH; 6.93, d, J=6.9 Hz, 1H, NH; 6.76, d,J=7.2 Hz, 1H, NH; 6.33, bs, 1H, NH; 6.26, bs, 1H, NH; 5.97, m, 1H,ArCH₂CH═CH₂; 5.63, m, 1H, CH₂CH═CH₂; 5.14–4.95, m, 4H, CH₂CH═CH ₂; 4.80,m, 1H, CHN; 4.71, dt, J=7.2, 7.2 Hz, 1H, CHN; 4.56–4.40, m, 2H, NH andCHN; 3.62, s, 3H, OCH₃; 3.46, d, J=8.1 Hz, 1H, ArCH ₂CH═CH₂; 3.43, d,J=7.2 Hz, 1H, ArCH ₂CH═CH₂; 3.32–2.94, m, 6H, NHCH ₂CH₂CH ₂ and ArCH₂;2.54, s, 3H, ArCH₃ (ortho to SO₂ attach); 2.51, s, 3H, ArCH₃ (ortho toSO₂ attach); 2.44, m, 4H, CH ₂CH═CH₂ and ArCH ₂CH₂; 2.06, s, 3H, ArCH₃;1.90, s, 3H, COCH₃; 1.74, t, J=6.3 Hz, 2H, ArCH₂CH ₂; 1.68, s, 9H,C(CH₃)₃; 1.58, m, 2H, NHCH₂CH ₂CH₂, 1.26, s, 6H, C(CH₃)₂.

Example 34 Preparation of Protected Cyclised Carbazole Peptoid Product

To a solution of the compound obtained in Example 33 (110 mg, 0.113mmol) in dry DCM (28 mL) was added Grubbs' ruthenium catalyst (9 mg,0.0113 mmol) and the reaction mixture was refluxed under a nitrogenatmosphere for 23 h. After this period the reaction solvent wasevaporated, and the crude product was chromatographed (PS with gradientelution to DCM:MeOH 10:1) and then triturated with diethyl ether/PS fromDCM to give a cyclised carbazole peptoid derivative (107 mg, 0.113 mmol,100%) as a cream solid, mp 190° C. (dec). Rf: 0.37 in 10% MeOH in DCM.Mass spectrum (ES⁺), m/z 942 (30%) [MH⁺].

Example 35 Preparation of6-acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophaneHCl

A solution of the cyclic carbazole derivative obtained in Example 34 (20mg, 0.0212 mmol) in TFA (2 mL) was stirred at room temperature under anitrogen atmosphere for 1.5 h. The TFA was removed by co-evaporationwith several portions of DCM. The crude product was dissolved in MeOH, a1M HCl-in-ether solution (0.04 mL, 0.0425 mmol) was added and thereaction mixture was stirred for 15 min. After this period the solventwas evaporated to a minimal volume and the product recrystallised fromether/PS over an ice bath to give6-acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophaneHCl (12 mg, 0.0196 mmol, 92%) as a pale brown solid, mp 222–224° C.(dec). Mass spectrum (ES⁺), m/z 576 (100%) [MH⁺]. HRMS calcd forC₃₀H₃₇N₇O₅+H: 576.2934. found: 576.2902.

Example 36

6-Acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophaneHCl (9S,12S) was prepared by hydrogenation of the compound of Example35.

Example 37

6-Acetamido-8,11-diaza-14-ene-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophaneHCl (9R,12S) was prepared according to the procedure for Example 35except the precursor containing a D-arginyl residue was used.

Example 38

6-Acetamido-8,11-diaza-9-(3-guanidinopropyl)-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophaneHCl (9R,12S) was prepared by hydrogenation of the compound of Example37.

Example 39

6-Acetamido-9-(4-aminobutyl)-8,11-diaza-14-ene-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophaneHCl (9S,12S) was prepared similarly to Example 35 from the correspondingprotected Fmoc-Lys-Pmb protected carbozole derivative with the initialdeprotection using anisole/TFA followed by piperidine

Example 39A

6-Acetamido-9-(4-aminobutyl)-8,11-diaza-1-tert-butoxycarbonyl-14-ene-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophaneHCl (9S,12S) was prepared similarly to Example 39 but deprotection ofthe lysine side chain was conducted using piperidine in dry THF at roomtemperature. The free base was converted to its hydrochloride salt usingHCl in ether with the compound isolated as a cream solid, mp ca 230° C.(dec). ¹H NMR, [500 MHz, (CD₃)₂SO] δ 8.84*, br d, J 7.5 Hz, NH-11;8.82*, br d, J 8.0 Hz, NH-11; 8.70, br d, J 7.5 Hz, NH-11; 8.63, br d, J7.5 Hz, NH-11; 8.49*, br d, J 10.0 Hz, NH-8; 8.47, br d, J 9.5 Hz, NHAc;8.41*, br d, J 8.5 Hz, NH-8; 8.38–8.28, m, NHAc; 8.24–8.16*, m, NH-11;8.14–7.93, m, 2H, ArH-2 and ArH-19; 8.04, br s, NH₂; 7.97*, br s, NH₂;7.83–7.77*, m, NH-8; 7.69, br d, J 8.0 Hz, NH-8; 7.57*, s, ArH-21; 7.55,s, ArH-20; 7.53, s, ArH-20; 7.50*, s, ArH-20; 7.49*, br d, J 8.5 Hz,NHAc; 7.41, s, ArH-21; 7.38–7.30*, m, ArH-3; 7.30, br d, J 8.0 Hz,ArH-18; 7.22, br d, J 6.5 Hz, NHAc; 7.16*, br d, J 8.0 Hz, ArH-3; 7.10,br d, J 8.0 Hz, ArH-3; 5.89–5.79, m, ArCH₂CH═CH (E isomer); 5.81–5.70,m, ArCH₂CH═CH* (Z isomer) and CHCH₂CH═CH; 5.72–5.62, m, CHCH₂CH═CH;5.65–5.42, m, CHCH₂CH═CH; 4.84*, br s, NCH-6; 4.62*, br d, J 3.5 Hz,NCH-6 and NCH-9; 4.46, br d, J 3.5 Hz, NCH-9 and NCH-12; 4.31*, br d, J8.0 Hz, NCH-12; 4.28*, br d, J 7.5 Hz, NCH-12; 4.18, br s, NCH-6;3.72–3.36, m, ArCH₂CH═CH; 3.65, s, OCH₃; 3.60*, s, OCH₃; 3.57*, s, OCH₃;3.22, −2.84, m, 2H, ArCH₂-5; 2.78–2.50, m, 2H, NCH ₂(CH₂)₃; 2.59, br d,J 11.0 Hz, CHCH ₂CH═CH; 2.42–2.28, m, CHCH ₂CH═CH; 2.33, br d, J 11.0Hz, CHCH ₂CH═CH; 1.90, s, COCH₃; 1.87, s, COCH₃; 1.84–1.45, m, 2H,N(CH₂)₃CH ₂; 1.77*, s, COCH₃; 1.73*, s, COCH₃; 1.67, s, 9H, C(CH₃)₃;1.62–1.40, m, 2H, NCH₂CH ₂(CH₂)₂; 1.32, m, N(CH₂)₂CH ₂CH₂; 1.21, m,N(CH₂)₂CH ₂CH₂.

Example 40

6-Acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophaneHCl (9S,12S) was prepared by hydrogenation of the compound of Example39.

Example 41

6-Acetamido-9-(4-aminobutyl)-8,11-diaza-14-ene-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophaneHCl (9R,12S) was prepared in the same manner as Example 39 except thatan amino acyl moiety containing a protected D-lysine residue wasutilised.

Example 42

6-Acetamido-9-(4-aminobutyl)-8,11-diaza-12-methoxycarbonyl-7,10-dioxo-[12](3,6)-1H-carbazolophaneHCl (9R,12S) was prepared by hydrogenation of the compound of Example 41

Example 43

Methyl8-acetamido-3,6-diaza-5-[3-guanidinopropyl]-4,7-dioxo-2-propyl-9-[3-(6-propyl)-9H-carbazole]nonanoateHCl (2S,5R) was prepared by hydrogenation and deprotection of the ringopened diene precursor of Example 37.

Hydrogenation of the compound obtained in Example 33 gave thecorresponding compound where the allyl groups had been reduced to propylgroups. This was deprotected according to the procedure of Example 35 toprovide a cream solid, mp 210° C.

¹H NMR, [500 MHz, (CD₃)₂SO, isomer ratio 69:31] δ 11.16*, br s, 0.3H,ArNH; 10.99, br s, 0.7H, ArNH; 8.33, br d, J 8.0 Hz, 0.7H, NH-6; 8.30,br d, J 6.5 Hz, 0.7H NHAc; 8.25*, br d, J 7.5 Hz, 0.3H, NH-3;8.21–8.11*, m, 0.6H, NH-6 and NHAc; 8.07, br d, J 7.5 Hz, 0.7H, NH-3;7.94, s, 1H, ArCH-4; 7.81, s, 1H, ArCH-5; 7.62–7.53*, m, 0.3H, NHCH₂;7.45, br s, 0.7 NHCH₂; 7.35, m, 2H, ArH-1 and ArH-8; 7.26, d, J 8.5 Hz,1H, ArH-2; 7.17, d, J 8.0 Hz, 1H, ArH-7; 6.85, v br s, 3H, NH(C═NH)NH ₂;4.56, m, 1H, NCH-8; 4.37*, dt, J 6.0, 7.5 Hz, 0.3H, NCH-5; 4.30–4.16, m,1.7H, NCH-2 and NCH-5; 3.61, s, 3H, OCH₃; 3.20–3.11*, m, 0.3H, ArCHH-9;3.15–3.05*, m, 0.6H, NCH ₂(CH₂)₂; 3.11–3.03, m, 0.7H, ArCHH-9;2.98–2.88, m, 0.7H, ArCHH-9; 2.93–2.83, m, 1.4H, NCH ₂(CH₂)₂;2.88–2.82*, m, 0.3H, ArCHH-9; 2.69, t, J 7.5 Hz, 2H, ArCH ₂CH₂CH₃; 1.77,s, 2.1H, COCH₃; 1.75*, s, 0.9H, COCH₃; 1.68–1.54, m, 2H, CHCH ₂CH₂CH₃;1.67–1.58*, m, 0.6H, C(CH₂)₂CH ₂; 1.65, m, 2H, ArCH₂CH ₂CH₃; 1.52–1.38*,m, 0.6H, NCH₂CH ₂CH₂; 1.48–1.36, m, 1.4H, N(CH₂)₂CH ₂; 1.34–1.17, m, 2H,CHCH₂CH ₂CH₃; 1.25–1.13, m, 1.4H, NCH₂CH ₂CH₃; 0.91, t, J 7.0 Hz, 3H,Ar(CH₂)₂CH ₃; 0.83, t, J7.0 Hz, 3H, CH(CH₂)₂CH ₃.

Example 44

Methyl8-acetamido-5-[4-aminobutyl]-3,6-diaza-4,7-dioxo-2-propyl-9-[3-(6-propyl)-9H-carbazole]nonanoateHCl (2S,5R) was prepared by hydrogenation and deprotection of the ringopened diene precursor of Example 41.

The uncyclised protected precursor to Example 41, was reduced byhydrogenation and then deprotected in the usual manner to yield a creamsolid, mp 160–162° C.

¹H NMR, [500 MHz, (CD₃)₂SO, isomer ratio 69:31] δ 11.16, br s, 0.7H,ArNH; 11.07*, br s, 0.3H, ArNH; 8.36, br d, J 6.5 Hz, 0.7H, NHAc; 8.32,br d, J 8.0 Hz, 0.7H, NH-6; 8.29*, br d, J 7.5 Hz, 0.3H, NH-3; 8.21*, brd, J 8.0 Hz, 0.3H, NHAc; 8.21*, br d, J 8.5 Hz, 0.3H, NH-6; 8.06*, br s,0.6H, NH₂; 8.02, br d, J 8.0 Hz, 0.7H, NH-3; 7.99, br s, 1.4H, NH₂;7.96*, s, 0.3H, ArH-4; 7.93, s, 0.7H, ArH-4; 7.81, s, 0.7H, ArH-5;7.79*, s, 0.3H, ArH-5; 7.37*, d, J 8.0 Hz, 0.3H, ArH-8; 7.35, d, J 8.5Hz, 1.4H, ArH-1 and ArH-8; 7.32*, d, J 8.5 Hz, 0.3H, ArH-1; 7.27*, d, J8.5 Hz, 0.3H, ArH-2; 7.25, d, J 8.5 Hz, 0.7H, ArH-2; 7.17, d, J 8.0 Hz,1H, ArCH-7; 4.57*, m, 0.3H, NCH-8; 4.53, dt, J 7.0, 7.5 Hz, 0.7H, NCH-8;4.34*, dt, J 5.5, 8.0 Hz, 0.3H, NCH-5; 4.22, m, 1H, NCH-2; 4.09, m,0.7H, NCH-5; 3.60, s, 3H, OCH₃; 3.18*, dd, J 13.5, 4.0 Hz, 0.3H,ArCHH-9; 3.05, dd, J 13.2, 7.5 Hz, 0.7H, ArCHH-9; 2.96, dd, J 13.2, 8.5Hz, 0.7H, ArCHH-9; 2.89*, dd, J 13.2, 10.5 Hz, 0.3H, ArCHH-9; 2.73*, brd, J 5.5 Hz, 0.6H, NCH ₂(CH₂)₃; 2.68, t, J 7.5 Hz, 2H, ArCH ₂CH₂CH₃;2.45, br s, 1.4H, NCH ₂(CH₂)₃; 1.79, s, 2.1H, COCH₃; 1.76*, s, 0.9H,COCH₃; 1.71–1.51, m, 2.6H, CHCH ₂CH₂CH₃ and N(CH₂)₃CH ₂*; 1.69–1.58, m,2H, ArCH₂CH ₂CH₃; 1.61–1.52*, m, 0.6H, NCH₂CH ₂(CH₂)₂; 1.61–1.48, m,0.7H, N(CH₂)₃CH ₂; 1.41–1.26, m, 2.7H, N(CH₂)₃CH ₂, NCH₂CH ₂(CH₂)₂ andN(CH₂)₂CH ₂CH₂*; 1.32–1.18, m, 2H, CHCH₂CH ₂CH₃; 0.91, t, J 7.0 Hz, 3H,Ar(CH₂)₂CH ₃; 0.90–0.82, m, 1.4H, N(CH₂)₂CH ₂CH₂; 0.82, t, J 7.0 Hz,2.1H, CH(CH₂)₂CH ₃; 0.81*, t, J 7.0 Hz, 0.9H, CH(CH₂)₂CH ₃.

Compounds Based on a 1,4-Substituted Phenyl Nucleus

General Synthetic Procedures

N-Boc & Pmc Deprotection (Procedure A)

The N-Boc or Pmc protected amine (1 equiv.) was stirred for 3 hours in1:1 DCM/TFA solution at room temperature. The solvent was removed underreduced pressure, and the residue was resuspended in a minimal volume ofmethanol. The solution was then treated with an excess of 1M HCl/ethersolution and the solvent again evaporated. The crude product waspurified by recrystallization/precipitation from DCM &/or MeOH byaddition of ether.

Peptide Coupling (Procedure B)

To a solution of the acid (1 equiv.) in DMF at room temperature wasadded HOBt (1.1 equiv.), EDCI (1 equiv.) and the amine (1.2 equiv.). Ifthe amine was a hydrochloride salt, DIPEA (1 equiv.) was also added. Themixture was allowed to stir for 16 hours before the reaction wasquenched with water until precipitation occurred. The solid wascollected by vacuum filtration, and washed thoroughly with water. Theamorphous product was dried over P₂O₅ to yield the desired peptide.

N-Fmoc Deprotection (Procedure C)

The Fmoc Protected amine (1 equiv.) was stirred in 1%piperidine/acetonitrile for 3 hours at room temperature. The solvent wasremoved under reduced pressure and the crude product was purified byflash column chromatography (15:1, DCM/MeOH) to yield the free amine.

Macrocyclization by Olefin Metathesis (Procedure D)

To a solution of the precursor tripeptide (1 equiv.) in DCM (to 0.004 M)was added Grubb's ruthenium catalyst (15 mol %) and the resultingsolution was heated at reflux for 48 hours before the solvent wasremoved by evaporation and the product isolated by flash columnchromatography (15:1, DCM/MeOH) to yield the corresponding macrocycle.

Example 45 Methyl(2S)-2{(1S)-1-[(1S)-2-(4-allyloxyphenyl)-1-methylcarboxamidoethylcarboxamido]-5-tert-butoxycarboxamidopentylcarboxamido}-4-pentenoate

To a solution of methyl(2S)-2-[(1S)-1-amino-5-tert-butoxycarboxamido]-4-pentenoate (782 mg,2.19 mmol) and (2S)-3-(4-allyloxyphenyl)-2-methylcarboxamidopropanoicacid (576 mg, 2.19 mmol) in DCM (10 mL) was added EDCI (420 mg, 2.19mmol) and a catalytic quantity of DMAP. The resulting mixture wasallowed to stir at room temperature for 16 hours before the reaction wasquenched by the addition of DCM (25 mL). The organic layer was washedwith brine (2×25 mL) and water (2×25 mL) and dried over MgSO₄, beforebeing concentrated by evaporation. The crude product was purified byflash column chromatography (25:1 DCM/MeOH) to afford methyl(2S)-2{(1S)-1-[(1S)-2-(4-allyloxyphenyl)-1-methylcarboxamidoethylcarboxamido]-5-tert-butoxycarboxamidopentylcarboxamido}-4-pentenoate(664 mg, 1.10 mmol, 50%) as a white solid. Mass Spectrum (ES, +ve) m/z503.4 (100%) [MH⁺ (less t-boc)], 603.4 (35%) [MH⁺]. HRMS calcd forC₃₁H₄₇N₄O₈ 603.3394. found 603.3397.

Example 46(5S)-5-[(1S)-2-(4-Allyloxyphenyl)-1-methylcarboxamidoethylcarboxamido]-5-[(1S)-1-methyloxycarbonyl-3-butenylcarbamoyl]pentylammoniumchloride

This ammonium salt was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from methyl(2S)-2{(1S)-1-[(1S)-2-(4-allyloxyphenyl)-1-methylcarboxamidoethylcarboxamido]-5-tert-butoxycarboxamidopentylcarboxamido}-4-pentenoate(104 mg, 0.170 mmol) to yield(5S)-5-[(1S)-2-(4-allyloxyphenyl)-1-methylcarboxamidoethylcarboxamido]-5-[(1S)-1-methyloxycarbonyl-3-butenylcarbamoyl]pentylammoniumchloride (55 mg, 0.10 mmol, 60%) as a yellow solid. Mass Spectrum (ES,+ve) m/z 503.3 (100%) [M⁺ less Cl⁻]. HRMS calcd for C₂₆H₃₉N₄O₆ 503.2870.found 503.2894.

Example 47 Methyl(7S,13S,10S)-10-(4-tert-butoxycarboxamidobutyl)-13-methylcarboxamido-9,12-dioxo-2-oxa-8,11-diazabicyclo[13.2.2]nonadeca-1(17),4,15,18-tetraene-7-carboxylate

The macrocyclic peptide was prepared using the general procedure forolefin metathesis (Procedure D) using methyl(2S)-2{(1S)-1-[(1S)-2-(4-allyloxyphenyl)-1-methylcarboxamidoethylcarboxamido]-5-tert-butoxycarboxamidopentylcarboxamido}-4-pentenoate(311 mg, 0.52 mmol) to yield methyl(7S,13S,10S)-10-(4-tert-butoxycarboxamidobutyl)-13-methylcarboxamido-9,12-dioxo-2-oxa-8,11-diazabicyclo[13.2.2]nonadeca-1(17),4,15,18-tetraene-7-carboxylate(228 mg, 0.40 mmol, 76%) as a brown solid. Mass Spectrum (ES, +ve) m/z475.3 (40%) [MH⁺ (less t-boc)], 575.3 (25%) [MH⁺].

Example 484-[(3S,9S,6S)-3-Methylcarboxamido-9-methyloxycarbonyl-4,7-dioxo-14-oxa-5,8-diazabicyclo[13.2.2]nonadeca-1(17),11,15,18-tetraen-6-yl]butylammmoniumchloride

This ammonium salt was synthesized using the general N-Boc deprotectionprocedure (Procedure A) using methyl(7S,13S,10S)-10-(4-tert-butoxycarboxamidobutyl)-13-methylcarboxamido-9,12-dioxo-2-oxa-8,11-diazabicyclo[13.2.2]nonadeca-1(17),4,15,18-tetraene-7-carboxylate(220 mg, 0.380 mmol) to yield4-[(3S,9S,6S)-3-methylcarboxamido-9-methyloxycarbonyl-4,7-dioxo-14oxa-5,8-diazabicyclo[13.2.2]nonadeca-1(17),11,15,18-tetraen-6-yl]butylammmoniumchloride (152 mg, 0.300 mmol, 79%) as a dark yellow solid. Mass Spectrum(ES, +ve) m/z 475.4 (100%) [M⁺ (less Cl⁻)].

Examples 49 Methyl(2S)-2-[(1S)-1-[(1S)-2-(4-allyloxyphenyl)-1-methylcarboxamidoethylcarboxamido]-5-di(tert-butoxycarboxamido)methyleneaminopentylcarboxamido]-4-pentenoate

To a solution of(5S)-5-[(1S)-2-(4-allyloxyphenyl)-1-methylcarboxamidoethylcarboxamido]-5-[(1S)-1-methyloxycarbonyl-3-butenylcarbamoyl]pentylammoniumchloride (41 mg, 0.081 mmol) in DCM (2 mL)N,N′-diBoc-N″-triflylguanidine (35 mg, 0.089 mmol), triethylamine (0.1mL) and DCM (2 mL). The resulting solution was allowed to stir overnightin a nitrogen atmosphere. The solvent was evaporated and the crudeproduct was purified by flash column chromatography (15:1, DCM/MeOH) toyield methyl(2S)-2-[(1S)-1-[(1S)-2-(4-allyloxyphenyl)-1-methylcarboxamidoethylcarboxarnido]-5-di(tert-butoxycarboxamido)methyleneaminopentylcarboxamido]-4-pentenoate(45 mg, 0.060 mmole, 74%) as an orange/yellow solid. ¹H NMR (CDCl₃, 300MHz): δ 8.26 (bs, 1H); 7.08 (t, J 8.4 Hz, 2H); 6.97 (m, 1H); 6.83 (t, J8.4 Hz, 2H); 6.73 (d, J 8.0 Hz, 1H); 6.57 (t, J 9.3 Hz, 1H); 6.03 (m,1H); 5.66 (m, 1H); 5.39 (d, J 17.3 Hz, 1H); 5.26 (d, J 10.1 Hz, 1H);5.10 (m, 2H); 4.51 (m, 5H); 3.74 (s, 3H); 3.33 (bs, 2H); 2.96 (ddd, J6.7, 7.2, 14.0 Hz, 2H); 2.52 (m, 2H); 1.97 (s, 3H); 1.47 (m, 6H); 1.54(s, 3H); 1.49 (s, 18H). ¹³C NMR (CDCl₃, 300 MHz): δ 171.7; 171.3; 171.2;170.9; 170.6; 163.2; 157.5; 156.0; 153.1; 151.4; 133.1; 132.0; 130.1;128.2; 119.2; 119.0; 117.5; 114.8; 83.2; 79.5; 68.7; 55.2; 53.1; 53.0;52.4; 40.7; 40.5; 37.2; 36.1; 32.0; 28.6; 28.3; 22.9. Mass Spectrum (ES,+ve) m/z 745.2 (100%) [MH⁺]. HRMS calcd for C₃₇H₅₇N₆O₁₀ 745.4136. found745.4105.

Example 50(5S)-5-[(1S)-2-(4-Allyloxyphenyl)-1-methylcarboxamidoethylcarboxamido]-5-[(1S)-1-methyloxycarbonyl-3-butenylcarbamoyl]pentylguanidiniumchloride

This salt was synthesized using the general N-Boc deprotection procedure(Procedure A) on the compound of Example 49. Mass Spectrum (ES, +ve) m/z545.3 (100%) [M⁺]. HRMS calcd for C₂₇H₄₁N₆O₆ 545.3088. found 545.3066.

Example 51 Methyl(7S,13S,10S)-10-[4-di(tert-butoxycarboxamido)methyleneaminobutyl]-13-methylcarboxamido-9,12-dioxo-2-oxa-8,11-diazabicyclo[13.2.2]nonadeca-1(17),4,15,18-tetraene-7-carboxylate

In an anlogous manner to Example 49, the compound of Example 48 wasconverted to its protected guanidine analogue. Isolated as anorange/yellow solid. Mass Spectrum (ES, +ve) m/z 717.4 (100%) [MH⁺].HRMS calcd for C₃₅H₅₃N₆O₁₀ 717.3823. found 545.3806.

Example 52Imino{4-[(3S,6S,9S)-3-methylcarboxamido-9-methyloxycarbonyl-4,7-dioxo-14oxa-5,8-diazabicyclo[13.2.2]nondeca-1(17),11,15,18-tetraen-6-yl]butylamino}methylammoniumchloride

Deprotection procedure (Procedure A) of Example 51 gave the desiredcompound as a yellow solid. Mass Spectrum (ES, +ve) m/z 517.4 (100%) [M⁺(less Cl⁻)]. HRMS calcd for C₂₅H₃₇N₆O₆ 517.2775. found 517.2765.

Examples 53–60

In an analogous manner, the series of compounds corresponding to thecompounds of Examples 45–52 but where the L-lysine was replaced withD-lysine were prepared.

Examples 61–64

A series of compounds corresponding to the compounds of Examples 45–48but where the L-allyl glycine was replaced with D-allyl glycine, andL-lysine was replaced with D-arginine were prepared in an analogousmanner to the compounds of Examples 45–48. The arginine was Pmcprotected.

Examples 65–68

In an analogous manner, the series of compounds corresponding to thecompounds of Examples 61–64 but where the D-arginine was replaced withL-arginine were prepared.

Compounds Based on a 1,3-Substituted Indole Nucleus

Nomenclature of cyclic peptoids based on a 1,3-substituted indolenucleus. These compounds are named as bridged compounds with the methenobridge between the atoms 1 and 15. The macrocyle is then label andnumbered as illustrated below.

Methyl1,2,5,6,7,9,10,12,13,14-octahydro-1,15-metheno-7,10-diaza-8,11-dioxo-9-4′(tert-butoxycarbonylamino)butyl-1-benzazacyclododecine-6-carboxylate

Example 69 Preparation of 1-Prop-2-enyl1-(1-prop-2-enyl)-indole-3-acetate and 1-Prop-2-enyl 1H-indole-3-acetate

Sodium hydride (1.0 g, 25.1 mmol, 2.2 molar equiv., 60% in paraffin) waswashed with petroleum spirit twice under a N₂ atmosphere before dry DMFwas added. A solution of 1H-indole-3-acetic acid (2.0 g, 11.4 mmol) inDMF under N₂ was added to this suspension at room temperature and themixture was stirred for half an hour. Allyl bromide (2.5 mL, 28.6 mmol,2.5 molar equiv) was added dropwise and the reaction mixture was stirredovernight at room temperature. The DMF was evaporated and the residuewas partitioned between diethyl (20 mL) and water (20 mL). The diethyllayer was separated and the aqueous layer was extracted further withdiethyl ether. The combined diethyl ether layers were washed with water,dried (Na₂SO₄) and evaporated. The crude product was chromatographed ona flash silica gel column (20% DCM in petroleum spirit as eluent) toproduce the diallyl derivative as an oil (1.9 g, 95%) and the allylester(90 mg) upon elution with 50% DCM in petroleum spirit. For 25: MS (CI)m/z 256 (100% MH⁺). HRMS (CI) calcd for C₁₆H₁₈NO₂: 256.1338. found:256.1338.

For the diallyl derivative: MS (CI) m/z 216 (100% MH⁺). HRMS (CI) calcdfor C₁₃H₁₄NO₂: 216.1024. found: 216.1021.

Example 70 Preparation of 1-(1-prop-2-enyl)-1H-indole-3-acetic acid

To a solution of the diallyl from example 69 (1.8 g, 7.2 mmol) was addedlithium hydroxide (0.3 g, 0.15M) dissolved in a ratio of 2.5:1 THF/water(35 mL). The reaction mixture was placed in ice and stirred at 0° C. for3 hours. The solvent of THF was evaporated and the crude was extractedwith diethyl and water. The aqueous layer was separated with diethyllayer and extracted with water. The combined aqueous layers wereacidified by 10% hydrochloride acid to pH less than 2. The aqueous layerwas then saturated with sodium chloride and extracted with DCM (20 mL),dried (Na₂SO₄) and evaporated. The titled compound (1.1 g, 74%) wasobtained as an oil. ¹H NMR (CDCl₃) δ=7.60 (d, J=8 Hz, 1 H, ArH-4), 7.30(d, J=8 Hz, 1 H, ArH-7), 7.22 (dt, J=8, 1 Hz, 1 H, ArH-6), 7.13 (dt,J=8, 1 Hz, 1 H, ArH-5), 7.08 (s, 1 H, ArH-2), 5.98 (ddt, J=17, 11, 5 Hz,1 H, CH═CH₂), 5.20* (dd, J=9, 1 Hz, 2 H, CH═CH ₂), 5.11 (dd, J=16, 1 Hz,2 H, CH═CH ₂), 4.68 (dd, J=5, 1 Hz, 2H, NCH ₂CH═CH₂), 3.80 (s, 2 H,CH₂C═O); ¹³C NMR δ=177.5 (C═O), 136.1 (ArC), 133.2 (CH═CH₂), 127.6(ArC), 126.8, 121.8 and 119.3 (ArCH), 118.9 (CH═CH₂), 117.4 and 109.6(ArCH), 106.4 (ArC), 48.8 (NCH₂), 31.0 (CH₂); MS (CI) m/z 216 (100%MH⁺). HRMS (CI) calcd for C₁₃H₁₄NO₂: 216.1024. found: 216.1039.

Example 71 Preparation ofN-[(1S)-1-[[[(1S)-1-methoxycarbonyl-3-butenyl]amino]carbonyl]-5(tert-butoxycarbonylamino)pentyl]-1-(1-prop-2-enyl)-1H-indole-3-acetamide

The compound of Example 70 (0.05 g, 0.2 mmol) in DCM (3 mL) was coupledto N-Boc-D-lysine-L-allylglycine methyl ester (0.08 g, 0.2 mmol) in thestandard manner to produce the titled compound (0.08 g, 100%) as asolid. ¹H NMR (CDCl₃) δ=7.52 (d, J=8 Hz, 1 H, ArH-4), 7.29 (d, J=8 Hz, 1H, ArH-7), 7.20 (t, J=8 Hz, 1 H, ArH-6), 7.10 (t, J=8 Hz, 1 H, ArH-5),7.06 (s, 1 H, ArH-2), 6.78 (d, J=8 Hz, 1 H, NH-3′), 6.21 (d, J=8 Hz, 1H, NH-6′), 5.97 (ddt, J=17, 11, 5 Hz, 1 H, NCH₂CH═CH₂), 5.61 (m, 1 H,CHCH₂CH═CH₂), 5.18 (d, J=10 Hz, 1 H, CH═CHH), 5.09–5.04 (m, 3 H, CH═CH₂+CH═CHH), 4.69 (d, J=6 Hz, 2 H, NCH ₂—CH═CH₂), 4.53 (m, 1 H, αCH-2′),4.43 (m, 1 H αCH-5′), 3.72 (s, 2 H, CH₂-8′), 3.68 (s, 3 H, OCH₃), 2.93(d, J=5 Hz, 2 H, NCH ₂(CH₂)₃), 2.53–2.35 (m, 2 H, CHCH ₂CH═CH₂),1.77–1.66 (m, 1 H, N(CH₂)₃CH ₂) 1.41 (s, 9 H, Boc), 1.45–1.27 (m, 4 H,N(CH₂)₃CH₂+NCH₂CH ₂(CH₂)₂), 1.15–1.08 (m, 2 H, N(CH₂)₂CH ₂CH₂).

Example 72 Preparation ofN-[(1S)-1-[[[(1S)-1-methoxycarbonyl-3-butenyl]amino]carbonyl]-5′-amino-pentyl]-1-(1-prop-2-enyl)-1H-indole-3-acetamide

The compound of Example 71, was deprotected in the standard manner toprovide the titled compound as a brown solid. mp 103–106° C.; MS (ES)m/z 455 (100% MH⁺), 326 (79% M⁺-(NHCH(CH₂CH═CH₂)COOCH₃). HRMS (ES) calcdfor C₂₅H₃₅N₄O₄: 455.2658. found: 455.2663.

Example 73 Preparation ofmethyl-1,2,5,6,7,9,10,12-octahydro-1,13-metheno-7,10-diaza-8,11-dioxo-9-4′(tert-butoxycarbonylamino)butyl-1-benzazacyclododecine-6-carboxylate

Ring closure of the compound of Example 71 in the standard manner gavethe cyclic compound as a brown amorphous solid. MS (ES) m/z 527 (45%MH⁺), 471 (56% MH⁺—CMe₃), 453 (74% M⁺-OC(CH₃)₃), 427 (100% MH⁺-Boc).HRMS (ES) calcd for C₂₃H₃₁N₄O₄: 527.2870. found: 527.2870.

Example 74 Preparation ofmethyl-1,2,5,6,7,9,10,12-octahydro-1,13-metheno-7,10-diaza-8,11-dioxo-9-4′-aminobutyl-1-benzazacyclododecine-6-carboxylate

Deprotection of the compound of Example 73 in the standard manner gavethe titled compound as a brown solid. mp 168–170° C.; ¹H NMR (CD₃OD, 500MHz) δ=7.39 (d, J=8 Hz, 1 H, ArH-14″), 7.27* (d, J=8 Hz, ArH-17″), 7.21(d, J=8 Hz, 1 H, ArH-17″), 6.98 (t, J=8 Hz, 1 H, ArH-16″), 6.93 (s, 1 H,ArH-18″), 6.88 (t, J=8 Hz, 1 H, ArH-15″), 5.78* (dd, J=10, 5 Hz, CH-3″),5.52 (dt, J=15, 5 Hz, 1 H, CH-3″), 5.40* (dd, J=10, 5 Hz, CH-4″),4.88–4.83 (dt, J=15, 8 Hz, 1 H, CH-4″), 4.59 (dd, J=9, 3 Hz, 1 H,CHH-2″), 4.36 (dd, J=9, 6 Hz, 1 H, CHH-2″), 4.20 (t, J=7 Hz, 1 H,CH-9″), 4.10 (dd, J=9, 5 Hz, 1 H, CH-6″), 3.67 (d, J=9 Hz, 1 H,CHH-12″), 3.51 (s, 3 H, OCH₃), 3.31 (d, J=9 Hz, 1H CHH-12″), 2.74 (dd, 2H, NCH ₂(CH₂)₃), 2.51–2.42* (m, CHH-5″), 2.41–2.34 (m, 1 H, CHH-5″),2.12 (ddd, J=14, 6 Hz, 1 H, CHH-5″), 1.69–1.49 (m, 2 H, N(CH₂)₃CH ₂),1.58–1.48 (m, 2 H, NCH₂CH ₂(CH₂)₂), 1.36–1.23 (m, 2 H, N(CH₂)₂CH ₂CH₂).

Example 75 Preparation ofmethyl-1,2,5,6,7,9,10,12-1,13-metheno-7,10-diaza-8,11-dioxo-9-4′(ditert-butoxycarbonylamino)pentylguanidine-1-benzazacyclododecine-6-carboxylate

Guanidation of the compound of Example 74 according to the generalprocedure of Example 49 gave the titled compound. MS (ES) m/z 669 (27%MH⁺). HRMS (ES) calcd for C₃₄H₄₉N₆O₈: 669.3612. found: 669.3624.

Example 76 Preparation ofmethyl-1,2,5,6,7,9,10,12-octahydro-1,13-metheno-7,10-diaza-8,11-dioxo-9-4′-pentylguanidine-1-benzazacyclododecine-6-carboxylate

Deprotection of the compound of Example 75 in the standard mannerproduced the titled compound (0.06 g, 75%) as a brown solid. mp 151–154°C.

Examples 77–84

A series of compounds corresponding to the compounds of Examples 69–76but where a propanoate was attached at the 3-position of the indolerather than an acetate were prepared in an analogous manner to thecompounds of Examples 69–76.

Examples 85–92

A series of compounds corresponding to the compounds of Examples 69–76but where a butanoate was attached at the 3-position of the indolerather than an acetate were prepared in an analogous manner to thecompounds of Examples 69–76.

Compounds Based on a 2,2′-Substituted Binaphthyl Nucleus

Example 93 Synthesis of (aR/S)-2′-allyloxy-1,1′-binaphth-2-ol

1,1′-binaphthol-2,2′-diol (4.8678 g, 17 mmol) in acetone (20 ml) wasstirred with 3 g of anhydrous granules potassium carbonate (3.0 g) andmolecular sieve (5.0 g) 3 Å for 1 h under nitrogen prior to the slowaddition of allyl bromide (2 ml). The reaction mixture was refluxed for24 h and then was left to cool. The mixture was filtered off and thesolid being washed with acetone until colourless filtrate appeared. Thecombined filtrate was evaporated to dryness and the residue was taken upin 50 ml of dichloromethane and filtered to remove any remainingpotassium salts. The compound was purified by chromatography usingdichloromethane/hexane (1:2), R_(f)=0.8. Yield 4.0 g, m.p. 111° C. litmp: 112.5–114, Nakamura et al., Helvetica Chimica Acta, 58(7), (1975),214–215.

Example 94 Synthesis of ethyl(aR/S)-(2′-allyloxy-1,1′-binaphth-2-oxy)ethanoate

Example 93 (3.631 g, 11.138 mmol) in dry acetone (10 ml) was stirredwith anhydrous potassium carbonate (2.35 g) for 1 h under nitrogen priorto the addition of the ethyl bromoacetate (1.86 g, 11.138 mmol, 1.24ml). After the reaction being stirred overnight the reaction mixture wasfiltered. The solid being washed repeatedly with acetone. The filtratewas evaporated to dryness and the residue was taken up in chloroform (50ml) then filtered. The product isolated as a colourless semisolid byusing column chromatography chloroform/hexane 20% increase to 60%.Yield: 4.33 g. MS, m/z for C₂₇H₂₄O₄: 413 (M+1) 100%; 339 (M⁺-COOC₂H₅)11%.

Example 95 Synthesis of(aR/S)-(2′-allyloxy-1,1′-binaphth-2-oxy)ethanoicacid

Example 94 (0.1386 g, 0.336 mmol) was dissolved in THF (0.047 M, 4 ml).To this ice-cooled solution was added a solution of lithium hydroxidemonohydrate (1.513 mmol, 0.063 g) in water (9 ml). The mixture wasallowed to gradually warm to room temperature and was stirred for 5 h.To the reaction mixture was added diethyl ether. The aqueous layer wasseparated and washed with ether (20 ml×2) and the combined ether layersextracted with water (50 ml×2). The combined aqueous layers wereacidified (dilute hydrochloric acid) then extracted with diethyl ether(20 ml×3) then dried over anhydrous magnesium sulfate. The filtrate wasevaporated to dryness to afford the required product as off whiteprecipitate, m.p. 77–80° C.

Example 96

Example 95 (0.2689 g, 0.700 mmol) and N_(ε)-Boc-D-lys-L-allylglycinemethyl ester (0.25 g, 0.700 mmol) were coupled in the normal manner togive white solid, m.p. 54–6° C. Yield 0.3 g. ¹H NMR (CDCl₃, 300 MHz) δ8.015–7.982 (d, 1H, J=5.7 Hz), 7.982–7.955 (d, 1H, J=5.7 Hz),7.910–7.886 (d, 1H, J=4.2 Hz), 7.886–7.860 (d, 1H, J=4.2 Hz),7.510–7.469 (d, 1H, J=9.3 Hz), 7.469–7.433 (d, 1H, J=9.0 Hz),7.396–7.100 (m, 6H), 6.638–6.609 (d, 1H—N, J=7.5 Hz), 6.491–6.461 (d,1H—N, J=7.8 Hz), 6.182 (dd, 1H, J₁=7.8, J₂=12.0 Hz), 5.699–5.520 (m, 2H,HC=allyl), 5.109–4.885 (m, 4H), 4.581–4.459 (m, 6H), 4.116–4.060 (m,1H), 3.685 (s, 3H), 2.980–2.865 (m, 2H), 2.570–2.350 (m, 2H), 1.679 (br,2H), 1.455 & 1.436 (s, 9H, R, S isomers), 1.350–1.200 (m, 2H),1.060–0.760 (m, 2H). MS, m/z for C₄₂H₄₉N₃O₈: 723 (M⁺) 25%; 722 (M⁺−1)100%; 348 18%.

Example 97:

Deprotection of Example 96 in the normal manner provided the product. ¹HNMR (DMSO-d₆, 300 MHz) δ: 8.290–8.216 (m, 1H), 8.055–8.022 (m, 2H),7.959–7.925 (m, 2H), 7.743 (br, 3H—N) 7.568–7.478 (m, 2H), 7.378–7.305(m, 2H), 7.269–7.190 (m, 2H), 7.050–6.870 (m, 3H), 5.801–5.605 (m, 2H),5.120–4.920 (m, 4H), 4.610–4.250 (m, 6H), 3.611, 3.602 (s, 3H, R & S),2.637 (br, 2H), 2.450–2.310 (m, 2H), 1.500–0.860 (m, 6H). MS, m/z: 625(M⁺+1) 100%; 626, 19%; 737 (M⁻+TFA) 66%.

Example 98

Cyclisation of Example 96 in the usual manner gave the product.

¹H NMR (CDCl₃, 300 MHz) δ: 8.103–7.810 (br, 1H), 8.04–7.97 (m, 2H),7.930–7.875 (m, 2H), 7.502 (dd, 1H, J₁=4.2, J₂=8.7 Hz), 7.390–7.315 (m,3H), 7.285–7.090 (m, 4H), 6.512 (dd, 1H, J₁=7.8, J₂=38.7 Hz), 6.135 (dd,1H, J₁=4.2, J₂=7.5 Hz), 5.733–5.523 (m, 2H), 5.110–5.880 (m, 4H),4.583–4.469 (m, 5H), 4.120–4.058 (m, 1H), 3.682 (s, 3H), 3.212 (dd, 2H,J₁=7.2, J₂=12.6 Hz), 2.577–2.363 (m, 2H), 1.502, 1.486 (2×s, 9H, Boc),1.458–1.354 (m, 2H), 1.018–0.810 (m, 4H). MS m/z for C₄₀H₄₅N₃O₈: 696(M⁺+1) 52%; 695 (M⁺) 44%; 694 (M⁺−1) 100%.

Example 99

Deprotection of Example 98 in the usual manner the product.

MS m/z for C₃₅H₃₈ClN₃O₆: 596 (M⁺) 100%; 597 40%.

Example 100

The compound was prepared by guanidation of Example 97 in the usualmanner.

¹HNMR (CDCl₃, 300 MHz) δ: 8.273–8.212 (br, 1H), 8.04–7.97 (m, 2H),7.930–7.875 (m, 2H), 7.502 (dd, 1H, J₁=4.2, J₂=8.7 Hz), 7.390–7.315 (m,3H), 7.285–7.090 (m, 4H), 6.512 (dd, 1H, J₁=7.8, J₂=38.7 Hz), 6.135 (dd,1H, J₁=4.2, J₂=7.5 Hz), 5.733–5.523 (m, 2H), 5.110–5.880 (m, 4H),4.583–4.469 (m, 5H), 4.120–4.058 (m, 1H), 3.682 (s, 3H, methyl), 3.212(dd, 2H, J₁=7.2, J₂=12.6 Hz), 2.577–2.363 (m, 2H), 1.502 (s, 9H, Boc),1.486 (s, 9H, Boc), 1.458–1.354 (m, 2H), 1.018–0.810 (m, 4H). MS, m/zfor C₄₈H₅₉N₅O₁₀: 867 (M⁺+1) 100%; 867 67%; 868 67%.

Example 101 Preparation of methyl(aR/S,2S,5R)-2-allyl-5-[2-({[(2′-allyloxy-1,1′-binaphthoxymethyl]carbonyl}amino)-3-aza-9-guanidino-4-oxononanoatehydrochloride

The compound was prepared by deprotection of Example 100 in the usualmanner. MS, m/z for C₃₈H₄₄ClN₅O₆: 666 (M⁺+1) 100%; 667 25%; 668 7%; 664100%; 665 55%.

Example 102

The compound was prepared by guanidation of Example 99 in the usualmanner, m.p. 108° C.

Example 103 Preparation of(aR,S,7R,10S)-6,9-diaza-3,15-dioxa-5,8-dioxo-7-(4-guanidinobutyl)-10-methoxycarbonyl-1(1,2),2(1,2)-dinaphthalenacyclopentadecaphane-12-enehydrochloride

The compound was prepared by deprotection of Example 102 in the usualmanner. MS, m/z for C₃₆H₄₀ClN₅O₆: 638 (M⁺+1) 100%; 639 55%.

Examples 104–113

A series of compounds corresponding to the compounds of Examples 94–103but where the corresponding butanoate was prepared rather than anethanoate were prepared in an analogous manner to the compounds ofExamples 94–103.

Example 104 Synthesis of ethyl(aR/S)-(2′-allyloxy-1,1′-binaphth-2-oxy)butanoate

MS, m/z for C₂₉H₂₈O₄: 441 (M⁺+1) 14.5%; 115 (CH₂CH₂CH₂COOC₂H₅ ⁺) 100%.

Example 105 Synthesis of(aR/S)-(2′-allyloxy-1,1′-binaphth-2-oxy)butanoic acid

MS, m/z for C₂₇H₂₄O₄: 412 (M⁺+1) 77.1%; 395 81.5%; 355 (M⁺−OCH₂CHCH₂)12.8%; 87 (CH₂CH₂CH₂COOH⁺) 100%.

Example 106

m.p. 90° C. ¹H NMR (CDCl₃, 300 MHz) δ: 7.985–7.850 (m, 4H), 7.466–7.300(m, 4H), 7.238–7.130 (m, 4H), 6.558 (t, 1H—N, J=7.5 Hz), 5.749–5.591 (m,2H, HC=allyl), 5.451 (dd, 1H—N, J₁=7.5, J₂=19.2 Hz), 5.117–4.930 (m, 4H,OCH₂), 4.640–4.540 (m, 3H), 4.275–3.840 (m, 3H), 3.725, 3.693 (s, 3H1:1), 3.08–2.950 (m, 2H), 2.578–2.450 (m, 2H), 1.965–1.570 (m, 10H),1.442, 1.424 (s, 9H, Boc, 1:1), 1.363–1.080 (m, 2H).

Example 107 methyl(aS/R,2S,5R)-2-allyl-10-(2′-allyloxy-1,1′-binaphth-2-oxy)-5-(4-aminobutyl)-3,6-diaza-4,7-dioxodecanoatehydrochloride

MS, m/z for C₃₉H₄₆ClN₃O₆: 652 (M⁺+1) 100%; 653 81%; 654 44%.

Example 108

MS, m/z for C₄₂H₄₉N₃O₈: 724 (M⁺+1) 76%; 725 40%; 768 100%; 624 (M⁺-Boc)20%; 593 38%; 521 48%.

Example 109

MS m/z for C₃₇H₄₂ClN₃O₆: 624 (M⁺+1) 100%; 625 42%; 622 52%; 623 17%.

Example 110

MS, m/z for C₅₀H₆₃N₅O₁₀: 894 (M⁺+1) 100%; 895 70%, 896 20%.

Example 111 Preparation of methyl(aS/R,2S,5R)-2-allyl-10-(2′-allyloxy-1,1′-binaphth-2-oxy)-3,6-diaza-5-(4-guanidinobutyl)-4,7-dioxodecanoatehydrochloride

MS, m/z for C₄₀H₄₈ClN₅O₆: 694 (M⁺+1) 92%; 695 15%; 693 22%; 692 35%.

Example 112

m.p. 95° C. (d). MS, m/z for C₄₈H₅₉N₅O₁₀: 866 (M⁺+1) 100%; 867 45%.

Example 113 Preparation of(aR/S,9R,12S)-8,11-diaza-9-(4-guanidinobutyl)-12-methoxycarbonyl-1(1,2),2(1,2)-dinaphthalena-3,17-dioxa-7,10-dioxoheptadecaphane-15-enehydrochloride

MS, m/z for C₃₈H₄₄ClN₅O₆: 666 (M⁺+1) 100%; 667 40%.

Biological Testing:

General Methods for Antibacterial Screens

Definitions

SA: Staphylococcus aureus

PA: Pseudomonas aeruginosa

KP: Klebsiella pneumoniae

SP: Streptococcus pneumoniae

Bacterial Strains Used:

Staphylococcus aureus (ATCC 6538P)

Pseudomonas aeruginosa (ATCC 27853)

Klebsiella pneumoniae (IP103623)

Streptococcus pneumoniae (IP53146)

Culture Media

Mueller-Hinton Broth Medium (MMB): MHB (Oxoid CM405) was prepared withfinal concentrations of 1 μg/mL MgCl₂ and 2 μg/mL CaCl₂. Culture mediumwas pre-warmed for approximately 2–3 hours at 37° C. before use.

Mueller-Hinton Agar medium (MHA): MHB containing 1.5% Agar (Merck Agar1.01614).

Blood Agar (BA): Oxoid PP 2001.

Maintenance of Bacteria

From thawed cryovials, P. aeruginosa, K. pneumoniae and S. aureus werestreaked onto Mueller Hinton Agar (MHA), and S. pneumoniae was streakedonto Blood Agar (BA), and plates were incubated overnight at 37° C. Foreach bacterial strain, 10 cryovials were prepared by looping severalcolonies into 0.5 mL of 20% glycerol solution. The cryovials wereimmediately stored at −140° C.

Preparation of Seed Cultures

A cryovial was removed from −140° C. storage and thawed at roomtemperature. An MHA plate was streaked with a loopful of bacterialsuspension and incubated overnight at 37° C. to create a parent plate(P1). A daughter plate (D1) was streaked from the parent plate andincubated overnight at 37° C. The parent plate was stored at 4° C. Aloop of colony from the daughter plate was used to inoculate a 125 mLflask containing 20 mL of Mueller Hinton Broth (MHB) containing 25 μg/mLCaCl₂.2H₂O and 12.5 μg/mL MgCl₂.6H₂O. The flask was shaken at 260 rpmfor 18 hours at 37° C. on an orbital incubator shaker. The parent plate(P1) was reused within 9 days to generate another daughter plate (D2),which, in turn, was used to inoculate a broth culture. Parent plateswere used twice (to generate D1 and D2 plates) before a new one wasprepared from the previously thawed cryovial. The second parent plate(P2) was used to generate two additional daughter plates using theprocedure outlined above before being discarded. Cryovials were usedtwice to prepare parent plates (P1 and P2) before being discarded.

Preparation of Standardised Inocula for Assays

Prepare a 1/10 dilution of Seed Cultures by adding 250 μl of thecultures to 2,250 μl of MHB in a disposable cuvette. Read OD₆₅₀ andmultiply OD₆₅₀ by a factor of 10 to calculate the optical density of theundiluted culture. Calculate the required dilution factor by dividingthe observed OD₆₅₀ by the standard OD₆₅₀ for each strain (previouslydetermined in assay optimisation studies).

Klebsiella pneumoniae standard OD₆₅₀ = 6.16 Pseudomonas aeruginosastandard OD₆₅₀ = 7.14 Staphylococcus aureus standard OD₆₅₀ = 4.75Streptococcus pneumoniae standard OD₆₅₀ = 5.18Prepare 10 mL of standardised inocula as illustrated by the followingexample:

Sample calculation—Klebsiella pneumoniae

OD₆₅₀=0.652 (1/10 dilution)

10×0.652=6.52

∴6.16/6.52=0.94

Add 0.94 mL of Klebsiella pneumoniae seed culture to 9.06 mL of MHB asthe first dilution.

Prepare sufficient volumes of the final inoculum cultures in pre-warmedMHB (37° C.) by diluting the standardised cultures to the required finalconcentration. The final dilutions used for each of the bacterialstrains were as follows:

K pneumoniae—10⁶ dilution;

P. aeruginosa—10⁶ dilution;

S. aureus—10⁸ dilution;

S. pneumoniae—10⁴ dilution.

Assay Procedure (For 96 Well Microtiter Plates)

Add 50 microlitres of liquid medium to each well of a 96 well microtitreplate. Dissolve test samples in liquid medium. Add 50 microlitres oftest sample in triplicate to the top row of the microtitre plate, andinclude a vancomycin control set. Also include a compound negativecontrol well set. Allow inoculated culture medium to incubate at 37° C.for 30 minutes, shaking at 130 rpm. Using a multichannel pipette, mixthe contents of the first row and transfer 50 microlitres of mixed brothsolutions to the next row, change tips and repeat until the last rowcontains diluted compound or control and discard 50 microlitres from thelast row. Each well should now contain 50 microlitres of dilutedcompound or negative control medium. Using a multistepper pipette add 50microlitres of inoculum to each well of the plate, save for one rowcontaining the compound negative control, to this row add 50 microlitresof liquid broth. Incubate plates at 37° C. for 18 hours, shaking at 100rpm in an environment of approximately 90% relative humidity. Resultswere recorded as the highest dilution of compound that preventedbacterial growth MIC).

The compounds of the invention showed MIC's of between 1 and 250 μg permL.

Results of Certain Compounds against S. aureus

Example MIC μg/ml  13A 4  15 8 (one isomer)  15A 16  15B 16  19A 4  21A16 (one isomer)  21A 64 (another isomer)  33A 32  36 32  37 64  38 32 39A 32  40 64  44 32 (one isomer)  44 64 (another isomer)  42 64  97 4 99 32 101 8 103 8 107 16 109 64 111 8 113 8

REFERENCES

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1. A compound of the formula (I):

wherein A is a 2,2′-dimethoxy-1,1′-binapthyl group or a 1,1′-binapthylgroup; X and Z are at the 3 and 3′ positions of the binapthyl group,respectively or at the 2 and 2′ positions of the binapthyl grouprespectively; Q is hydrogen, C₁–C₁₂ straight chain, branched or cyclicalkyl substituted with one or more hydroxy groups, or a mono- ordi-saccharide moiety; Z is —CR¹⁰R¹¹—, —NR¹²—, —C(O)O—, —C(O)NR¹²— or—O—, where R¹⁰ and R¹¹ are independently selected from hydrogen,hydroxy, C₁–C₆ alkyl, C₆–C₁₀ aryl, C₁–C₆ alkoxy and —N(R¹³)₂ and whereeach R¹³ is independently selected from hydrogen and C₁–C₆ alkyl, andwhere R¹² is selected from hydrogen and C₁–C₆ alkyl; R¹ is selected fromhydrogen, hydroxy, C₁–C₆ alkyl, C₁–C₆ alkoxy, —N(R¹³)₂ and—N(R¹²)—COR¹⁴; where R¹² and R¹³ are as defined above, and where R¹⁴ isselected from hydrogen, hydroxy, C₁–C₆ alkyl, C₁–C₆ alkoxy and —NR¹²; R²is selected from hydrogen, hydroxy, C₁–C₆ alkyl, C₁–C₆ alkoxy, —N(R¹³)₂and —N(R¹²)—COCHR^(2a)R^(2b); where R^(2a) and R^(2b) are selected fromhydrogen, hydroxy, C₁–C₆ alkyl, C₁-–C₆ alkoxy, —N(R¹³)₂ and—N(R¹²)—COR¹⁴; where R¹², R¹³ and R¹⁴ are as defined above; R³, R⁴ andR⁵ are independently selected from hydrogen, C₁–C₆ alkyl and α sidechains of α-amino acids; R⁶ is —CO₂R¹⁵, —CONHR¹⁶, —CONHOR¹⁶, —CONHNHR¹⁶,—SO₂N(R¹⁶)₂, —SO₂R¹⁷ or —P(O)(OR¹⁸)(OR¹⁸) where each R¹⁵, R¹⁶, R¹⁷ andR¹⁸ is independently selected from hydrogen, C₁–C₆ alkyl, C₃–C₇cycloalkyl, C₆–C₁₀ aryl and C₇–C₁₀ arylalkyl; B is an α-amino acidresidue, a β-amino acid residue or an α,α-disubstituted amino acidresidue, such residue forming amide linkages with the adjacentmolecules; W is —O— or CR¹⁰R¹¹ where R¹⁰ and R¹¹ are as defined above; Yis an optionally substituted amino group, a moiety containing anoptionally substituted amino group or a salt thereof;

 is a single or double bond; R⁷ and R^(8a) are hydrogen or are absent if

 is a double bond; and R^(8b) and R⁹ are hydrogen, and X is selectedfrom (CR¹⁰R¹¹)_(u), —(CR¹⁰R¹¹)_(u)—CH═CH—, —NR¹²(CR¹⁰R¹¹)_(u)—,—(CR¹⁰R¹¹)_(u)NR¹², —O(CR¹⁰R¹¹)_(u)—, —(CR¹⁰R¹¹)_(u)O— or—O(CR¹⁰R¹¹)CH═CH— where R¹⁰, R¹¹ and R¹² are as defined above; or R^(8b)and R⁹ together form a covalent bond between X and the carbon to whichR^(8b) is attached, and X is selected from (CR¹⁰R¹¹)_(x),—NR¹²(CR¹⁰R¹¹)_(x)—, —(CR¹⁰R¹¹)_(x)NR¹²—, —O(CR¹⁰R¹¹)_(x)— or—(CR¹⁰R¹¹)_(x)O—, where R¹⁰, R¹¹ and R¹² are as defined above; n, m, rand t are independently selected from 0 or 1; s is an integer selectedfrom 0 to 3; p is an integer selected from 0 to 6, provided that when Wis —O—, p is at least 1; and u, x and q are independently selected from0 to 4; or a pharmaceutically acceptable salt thereof.
 2. A compound ofclaim 1 wherein each R¹ is H; and R² is —NH—COCHR^(2a)R^(2b).
 3. Acompound according to claim 1 wherein Q is hydrogen.
 4. A compoundaccording to claim 1 wherein Z is —CH₂— or —O—.
 5. A compound accordingto claim 1 wherein s is 0, 1 or 2 and each R¹ is independently selectedfrom hydrogen or hydroxy.
 6. A compound according to claim 1 wherein R²is hydrogen, hydroxy or N(R¹²)COR^(2a)R^(2b).
 7. A compound according toclaim 1 wherein R³ is hydrogen.
 8. A compound according to claim 1wherein B is absent or a D- or L-alanyl residue, a D-lysinyl residue, aD-arginyl residue or a D-homoarginyl residue.
 9. A compound according toclaim 1 wherein Y is selected from a group consisting of: —N(R¹³)₂,—N(R¹²)—COR¹⁴, —NR¹³C(═NR¹³)N(R¹³)₂, —C(═NR¹³)N(R¹³)₂,—NR¹³C(═O)N(R¹³)₂, —N═NC(═NR¹³)N(R¹³)₂, NR¹³NR¹³C(═O)NHN(R¹³)₂,—NR¹³C(═)NHN(R¹³)₂, wherein R¹² and each R¹³ is independently selectedfrom hydrogen and C₁–C₆ alkyl and R¹⁴ is selected from hydrogen,hydroxy, C₁–C₆ alkyl, C₁–C₆ alkoxy and NR¹²; and a 3–8-memberedN-containing cyclogroup.
 10. A compound according to claim 9 wherein Yis an unsubstituted amino group or a guanidino group, or theirhydrochloride salts.
 11. A compound according to claim 1 wherein R⁶ isCO₂R¹⁵ where R¹⁵ is C₁–C₆alkyl or C₇–C₁₀arylalkyl.
 12. A compoundaccording to claim 11 wherein R¹⁵ is methyl or benzyl.
 13. A compoundaccording to claim 1 wherein R^(8b) and R⁹ are hydrogen and X is—(CR¹⁰R¹¹)_(u)—, —O(CH2)_(u)-, —CH═CH—, —O(CR¹⁰R¹¹)CH═CH— or—CR¹⁰R¹¹—CH═CH— where R¹⁰ and R¹¹ are hydrogen and u is an integerselected from 2 or
 3. 14. A compound according to claim 1 wherein R^(8b)and R⁹ together form a covalent bond between X and the carbon to whichR^(8b) is attached and X is —(CR¹⁰R¹¹)_(x)— or —O(CH2)_(x)- wherein R¹⁰and R¹¹ are hydrogen and x is an integer from 1 to
 4. 15. A compoundaccording to claim 1 selected from benzyl(aR/S,2S,5R)-8-acetamido-2-allyl-9-{3-[3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl]}-3,6-diaza-5-(4-{[(tert-butoxy)carbonyl]amino}butyl)-4,7-dioxononanoate;(aR/S,7R,10S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-enehydrochloride;(aR/S,7R,10S)-4-acetamido-7-(4-aminobutyl)-6,9-diaza-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphanehydrochloride;(aR/S,7R,10S)-4-acetamido-6,9-diaza-10-benzyloxycarbonyl-7-(4-{[(tert-butoxy)carbonyl]amino}butyl)-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-ene;methyl(aR/S,2S,5R)-8-acetamido-2-allyl-9-[3-(3′-allyl-2,2′-dimethoxy-1,1′-binaphthyl)]-3,6-diaza-5-(3-guanidinopropyl)-4,7-dioxononanoatehydrochloride;(aR/S,7S,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-enehydrochloride;(aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphane-12-enehydrochloride;(aR/S,7R,10S)-4-acetamido-6,9-diaza-7-(3-guanidinopropyl)-10-methoxycarbonyl-1(1,3),2(1,3)-di(2-methoxynaphthalena)-5,8-dioxocyclotetradecaphanehydrochloride; methyl(aR/S,2S,5R)-2-allyl-5-[2-({[(2′-allyloxy-1,1′-binaphthoxymethyl]carbonyl}amino)-3-aza-9-guanidino-4-oxononanoatehydrochloride;(aR/S,7R,10S)-6,9-diaza-3,15-dioxa-5,8-dioxo-7-(4-guanidinobutyl)-10-methoxycarbonyl-1(1,2),2(1,2)-dinaphthalenacyclopentadecaphane-12-enehydrochloride; methyl(aS/R,2S,5R)-2-allyl-10-(2′-allyloxy-1,1′-binaphth-2-oxy)-5-(4-aminobutyl)-3,6-diaza-4,7-dioxodecanoatehydrochloride; methyl(aS/R,2S,5R)-2-allyl-10-(2′-allyloxy-1,1′-binaphth-2-oxy)-3,6-diaza-5-(4-guanidinobutyl)-4,7-dioxodecanoatehydrochloride; or(aR/S,9R,12S)-8,11-diaza-9-(4-guanidinobutyl)-12-methoxycarbonyl-1(1,2),2(1,2)-dinaphthalena-3,17-dioxa-7,10-dioxoheptadecaphane-15-enehydrochloride.
 16. A composition comprising a compound of formula (I)according to claim 1, or a pharmaceutically acceptable salt thereoftogether with one or more pharmaceutically acceptable carriers oradjuvants.
 17. A method of treating a bacterial infection in a mammalcomprising administering an effective amount of a compound of formula(I) according to claim 1, or a pharmaceutically acceptable salt thereof.18. A method according to claim 17 where the mammal is a human.
 19. Amethod according to claim 17 wherein the bacterial infection is causedby Gram positive bacteria.
 20. A method according to claim 19 whereinthe bacterial infection is caused, by vancomycin resistantStaphylococcus aureas.